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Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism
Open accessAbstract
Significance: Cholesterol is important for normal brain function and it is believed that astrocytes produce most brain cholesterol. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in the transcription factor sterol regulatory element-binding protein 2 (SREBP2). Using a mouse model in which SREBP2 has been knocked out in astrocytes, we show that astrocyte SREBP2 is required for normal brain development and behavior. Furthermore, this results in a shift in metabolism driven by increased brain glucose oxidation. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain development and function, and altered brain cholesterol synthesis may contribute to the interaction between diabetes and altered brain function.
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Written from the paper’s full text.
TL;DR
Astrocyte-specific loss of SREBP2-mediated cholesterol synthesis impairs neurite outgrowth, brain development, behavior, and whole-body energy metabolism in mice. The metabolic phenotype includes reduced adiposity and a shift toward carbohydrate oxidation driven by increased brain glucose oxidation.
Key findings
- Srebf2 knockdown in C6 glioma cells reduced total and cleaved SREBP2 protein by ∼60% and cholesterol content in cells and media by ∼50%; control glia increased GT1-7 neurite length by 46%, whereas Srebf2-knockdown glia increased it by only 15%.
- G-SB2KO mice had microcephaly with a 28% reduction in brain weight (343 ± 11 mg vs. 478 ± 5 mg in controls, P < 0.001), impaired nest-building (P < 0.05), and memory retention defects (10.2 ± 1.1 vs. 6.2 ± 0.8 wrong turns, P < 0.01); balance-beam crossing time was 2.7 ± 0.4 vs. 1.9 ± 0.1 s (P < 0.05) with more foot slips (2.3 ± 0.7 vs. 0.8 ± 0.2, P < 0.05).
- At 9 months, male G-SB2KO mice had a 25% reduction in lean mass and 72% reduction in fat mass; visceral fat was reduced 79% and subcutaneous fat 66%.
- Dark-phase respiratory exchange ratio was higher in G-SB2KO mice (0.92 ± 0.02 vs. 0.81 ± 0.02, P < 0.001), and brain glucose oxidation increased to 96.8 ± 1.1% vs. 91.4 ± 1.0% in controls (P < 0.01), while gastrocnemius muscle oxidation decreased to 29.8 ± 3.1% vs. 58.6 ± 9.5% (P < 0.01).
Methods
- In vitro: C6 rat glioma cells were stably infected with lentiviral Srebf2 shRNA or scrambled shRNA; GT1-7 hypothalamic cells were cocultured in transwells, and neurite length was measured using ImageJ/NeuronJ.
- In vivo: astrocyte-specific conditional SREBP2 knockout mice (hGFAP-cre;Srebf2 lox/lox, G-SB2KO) were compared with littermate controls using behavioral tests (nest building, Stone T-maze, balance beam), DXA/necropsy, metabolic cages, high-fat diet, and cold exposure.
- Hyperinsulinemic clamps with [U-13C]glucose were performed at blood glucose ∼135 mg/dL; tissue glucose oxidation was assessed as the ratio of 13C2 acetyl CoA to 13C3 alanine, reflecting PDH flux relative to CS flux.
Limitations
- The paper states that some astrocytes do not express Gfap unless activated, some adult neural progenitor cells express Gfap, and GFAP-negative astrocytes could become GFAP-positive with aging or late neurogenesis could produce neurons with Srebp2 KO.
- The paper states that the reason for increased brain glucose requirement is not clear.
- Evident from the text: the in vitro work uses C6 glioma and GT1-7 cell lines rather than primary astrocytes/neurons, and neuronal SREBP2 compensation may partially rescue the astrocyte KO, complicating interpretation of the full phenotype.
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48 Own result · 19 Sources not found · 18 Own interpretation · 8 No basis given · 2 Own method
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In the paper
“Histological examination revealed that this result was because of smaller size of adipocytes in the white and brown fat pads of G-SB2KO mice.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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“After 7 wk, the G-SB2KO mice only gained 7 g of weight compared with nearly 15 g in the controls (Fig. S8A) (P < 0.01 for weeks 0-6, P = 0.02 for week 7).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
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“In the G-SB2KO mice, brain glucose oxidation increased even further to 96.8 ± 1.1% (P < 0.01)”
- Also stated in: § Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments). · plain
“Glucose oxidation is increased in G-SB2KO brain.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
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- Also stated in: § Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments). · plain
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In the paper
“Gross examination and dissection revealed microcephaly with a 28% reduction in brain weight (3-mo-old males, 343 ± 11 mg vs. 478 ± 5 mg in controls, P < 0.001) (Fig. 2 A and B)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
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“Knockdown of Srebf2 decreased both the total and cleaved forms of SREBP2 protein by ∼60% (Fig. S1A)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 in Astrocytes Is
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“Indeed, G-SB2KO mice had significantly lower liver weight than controls (0.79 ± 0.04 vs. 1.07 ± 0.08 g, P = 0.01) (Fig. 4A), as well as a trend toward decreased muscle weight.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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“This finding cannot be attributed to an increase in activity or increased sympathetic nervous system activity.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“G-SB2KO mice also show an inability to accumulate fat on either a normal diet or high-fat diet.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“Although the mice are fully viable”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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In the paper
“and that this is lost by knockdown of SREBP2 in the glia cells”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“with the greatest reductions in regions rich in astrocytes.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“We find that loss of astrocyte-SREBP2 in vitro results in impaired dendrite outgrowth from neurons in coculture.”
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- Rests on an assumption: C6 glioma cells are a valid model for astrocytes in the coculture experiments.
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In the paper
“whereas this ratio decreased in gastrocnemius muscle from 58.6 ± 9.5% in controls to 29.8 ± 3.1 in G-SB2KO mice (P < 0.01)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
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“we show that in culture glial-conditioned media can support neurite outgrowth”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [11]
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“SREBP2 KO in astrocytes also results in a major increase in RER in the fed state”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“Despite the partial rescue, G-SB2KO mice exhibit a broad array of behavioral changes.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“which still contain abundant astrocytes”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“G-SB2KO mice were also protected from weight gain associated with aging.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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In the paper
“As shown in Fig. 3B, G-SB2KO mice showed a significant impairment in nest-building quality (P < 0.05).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
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“However, when mice were challenged with 4 °C cold exposure for 24 h to activate brown fat, G-SB2KO mice were able to maintain body temperature similar to controls (Fig. S5A).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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“The difference in body weight and fat accumulation between control and G-SB2KO mice is not accounted for by an increase in energy expenditure or by caloric loss in urine or stool.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“As expected, in controls the highest carbohydrate flux was in the brain, with 91.4 ± 1.0% of the labeled glucose in 13 C 2 acetyl CoA, and other tissues showing lower rates (Fig. 5A).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
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“As early as 5 wk of age, male G-SB2KO mice showed lower body weights compared with control littermates (20.0 ± 0.7 vs. 23.7 ± 0.4 g, P = 0.001).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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“The most striking difference in the metabolic cage assessment, however, was a dramatic increase in the respiratory exchange ratio (RER) in the G-SB2KO mice during the dark (feeding) phase of the study, (0.92 ± 0.02 vs. 0.81 ± 0.02, P < 0.001) (Fig. 4 E and F).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
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“the brains of homozygous G-SB2KO mice, which still contain abundant astrocytes, are reduced in size by about 30%”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“When GT1-7 cells were grown in transwells with control C6 shScramble cells above them, there was a 46% increase in average neurite length compared with GT1-7 cells grown alone (Fig. 1 B and C), indicating that glial cells produce a factor that enhances neurite growth.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Significance
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In the paper
“and are protected from age-and high-fat diet-induced obesity.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“in the motor cortex and hippocampus there was a >50% reduction in Srebf2 transcript levels (Fig. 2D), indicating the high efficacy of gene recombination in these areas.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
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“The weight difference was also present in females and increased with time, such that by 4 mo of age, female G-SB2KO mice weighed 20% less than controls (19.6 ± 0.7 vs. 24.1 ± 1.1 g, P < 0.01) (Fig. S4A).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
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“The differences in RER were weight-independent, as evidenced by a similar difference in RER between weight- matched control and G-SB2KO mice (Fig. S7 D and E).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
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“These mice also have a surprising reduction of body mass”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“Serial sections through the brain showed that volume loss was most dramatic in the cortex, hippocampus, and white-matter tracks, such as the corpus callosum (Fig. 2C)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
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“Cholesterol content per gram tissue, however, shows only a modest reduction”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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“with no significant changes in ratio in heart, liver, white or brown fat (Fig. 5B and Fig. S9F).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
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In the paper
“and are protected from age-and high-fat diet-induced obesity.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
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In the paper
“Loss of SREBP2 from glia inhibits neurite outgrowth.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
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In the paper
“G-SB2KO mice have multiple neurologic defects.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
plainn = 12 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Distribution of nesting scores, n = 12 control, 17 G-SB2KO, P < 0.05 by Wilcoxon Rank Sum.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
plainn = 12 ·- Asserted: passes — The authors put it forward as true.
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“Furthermore, we and others have shown that knockdown or inhibition of cholesterol synthesis from neurons creates insulin resistance in those cells (33,34)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [34]
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boosteddirect- Asserted: passes — The authors put it forward as true.
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“There is a strong link between diabetes, insulin resistance in the brain, and AD (24)(25)(26)(27).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [25]
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- Not matchedcites [26]
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- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“Cholesterol is important for normal brain function.”
What the sources say
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the smaller fat pads in G-SB2KO mice could not be attributed to brown fat activation or browning of the white fat pads.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating glial cholesterol production as an important contributor to this phenomenon.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A similar increase in RER during the first half of the dark cycle is observed in mice in which brain cholesterol synthesis was disrupted by heterozygous KO of SCAP (8).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“because of increased SREBP2 expression in neurons compensating for the loss in astrocytes.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This shift in substrate oxidation toward carbohydrates in fed G-SB2KO mice was observed in younger female mice and was confirmed in 9-mo-old male mice as well (Fig. S7B).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: An increase in RER reflects a shift in substrate oxidation toward carbohydrates.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that neurons were compensating for the loss of cholesterol synthesis by astrocytes.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating a shift toward carbohydrate metabolism driven by an increase in brain glucose oxidation.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The brain is a near obligate user of carbohydrates for fuel.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data, together with the RER data, suggest that the increased whole-body carbohydrate metabolism in G-SB2KO mice is being driven by brain glucose oxidation at the expense of the muscle.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The brain is a near obligate user of carbohydrates for fuel.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Instead, it appears to be because of increased carbohydrate use by the brain”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The brain is a near obligate user of carbohydrates for fuel.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3)(4)(5).”
What the sources say
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As a result, areas of the brain that have a lower density of astrocytes may be less vulnerable to the disruption in astrocyte cholesterol synthesis.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This broad set of behavioral defects is in line with the idea that loss of cholesterol production by astrocytes results in a generalized reduction in the quality and quantity of neuronal synapses.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, despite their preference to use carbohydrate, G-SB2KO mice retain enough metabolic flexibility to metabolize a primarily fat-based diet.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“implying an insulin-cholesterol relationship in this patient population (32).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“large randomized controlled clinical trials using cholesterol-lowering statin drugs showed little impact on AD progression (14).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting a feed-forward connection between diabetes and AD.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our data suggest that lowering brain cholesterol levels could actually have a detrimental effect on brain function.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Cholesterol does not significantly cross the blood-brain barrier.
In the paper
“Preliminary clinical trials using intranasal insulin in patients with AD, but not diabetes, have shown some effectiveness on dementia symptoms (31)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“arguing that lack of insulin or insulin activity, rather than surplus insulin, may be a contributor to diabetes-associated AD.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 26
- The quote only partly states this claim. 1
- Probably not a substantial claim. 11
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“caused an ∼50% reduction in cholesterol content in the C6 glioma cells, as well as in cholesterol secreted into the media (Fig. 1A).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Significance
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Necropsy revealed differences in all fat depots, with a 79% decrease in visceral fat pad weight (0.36 ± 0.09 vs. 1.68 ± 0.54 g, P < 0.05) (Fig. 4A), a 66% decrease in subcutaneous (SQ) fat pad weight (0.30 ± 0.06 vs. 0.87 ± 0.18 g, P = 0.01), and a 48% reduction in interscapular brown fat weight (0.45 ± 0.02 vs. 0.86 ± 0.20 g, P = 0.07).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The impact of SREBP2 loss from astrocytes on brain function is evident by multiple measures, including social behavior, learning and memory, and motor coordination.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The impairment in G-SB2KO mice was not because of muscle weakness, as there was no difference between groups in grip strength (Fig. S3D).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Homozygous SREBP2 KO pups (hGFAP-cre;Srebf2 lox/lox , designated G-SB2KO) were born at normal Mendelian ratios and, in contrast to mice with KO of SCAP from astrocytes or whole brain (8, 17), were healthy and viable for the length of the study (10 mo).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: hGFAP-cre specifically targets astrocytes and not other cell types.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Nonetheless, most defects were already present by 3 mo of age and were stable until at least 10 mo of age.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although all of the control mice were able to be trained, one-third of KO mice could not be trained to complete the maze (P < 0.05) (Fig. 3C).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Motor coordination-that is, the time to cross a 12-mm by 50-cm balance beam-was also significantly increased (2.7 ± 0.4 vs. 1.9 ± 0.1 s, P < 0.05), and KO mice had significantly more foot slips than the controls (2.3 ± 0.7 vs. 0.8 ± 0.2 foot slips, P < 0.05) (Fig. 3E).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although food intake over 72 h was equivalent in G-SB2KO and controls (9.98 ± 0.78 vs. 9.30 ± 0.76 g, P = 0.56) (Fig. S7A), the G-SB2KO mice were less active during the light phase (40 ± 13 vs. 196 ± 35 beam breaks per 15 min, P < 0.01) (Fig. 4C). This resulted in a decrease in VO 2 during the same period (3,874 ± 88 vs. 4,406 ± 224 mL•h•kg -1 lean body weight, P = 0.05) (Fig. 4D).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Respiratory Exchange Ratio Is Dramatically Increased in G-SB2KO
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, there were no differences is blood pressure or pulse rate between the groups and no differences in urine metanephrine or normetanephrines (Table S1).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More importantly, when retested 1 wk after the learning trials, the G-SB2KO mice made significantly more mistakes than the controls, indicating a defect in memory retention (10.2 ± 1.1 vs. 6.2 ± 0.8 wrong turns for controls, P < 0.01) (Fig. 3D).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glucose absorption as determined by oral glucose tolerance tests was the same between control and G-SB2KO mice (Fig. S6B), as were intraperitoneal glucose tolerance tests (Fig. S6C).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under these conditions there was also similar whole-body glucose uptake [64.6 ± 3.6 vs. 71.0 ± 9.0 mg/(kg-min), P = 0.44] (Fig. S9C), suppression of endogenous glucose production (72.6 ± 14.5 vs. 76.6 ± 16.9%, P = 0.87) (Fig. S9D), and suppression of non- esterified fatty acids (63.0 ± 7.1 vs. 69.7 ± 9.0%, P = 0.60) (Fig. S9E) in the G-SB2KO and control mice.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Glucose Oxidation in G-SB2KO Tissues.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, when GT1-7 cells were cocultured with Srebf2-knockdown glioma cells, there was only a 15% increase in neurite length, consistent with the important factor being cholesterol.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Significance
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
- Rests on an assumption: Cholesterol is the key mediator of the effect of glial cells on neurite outgrowth.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At 9 mo of age, DXA assessment of the male mice demonstrated a significant 25% reduction in lean mass (22.2 ± 1.0 vs. 29.9 ± 1.3 g in controls, P < 0.001) and an impressive 72% reduction in fat mass (3.9 ± 0.8 vs. 14.1 ± 1.2 g, P < 0.001) (Fig. S4C).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fecal calorie content, assessed by bomb calorimetry, also showed no evidence of malabsorption in KO mice (Table S1), and there was no evidence of glucose in the urine of any of the mice.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > G-SB2KO Mice Have Altered Body Composition.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In G-SB2KO mice there was a decrease in SREBP2 staining in astrocytes, but a large increase in neurons, suggesting that neurons were compensating for the loss of cholesterol synthesis by astrocytes.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > SREBP2 Expression in Astrocytes Is Required for Normal Brain
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Four of the 12 G-SB2KO mice could not be trained to complete the maze.All 11 controls were trainable.P < 0.05 by two-proportion test.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
plainn = 12 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“G-SB2KO mice have altered body composition and metabolism.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2).”
What the sources say
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“Additionally, astrocytes are able to use a wider range of fuels than neurons, such as acetate (23).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo, loss of SREBP2 in astrocytes alters brain development, resulting in abnormal social, memory, and motor behaviors, as well as multiple metabolic defects, including reduction in adiposity and an altered balance of carbohydrate and lipid oxidation, both at the whole-body level and in the brain.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- The authors state this as an assumption: Astrocytes produce most brain cholesterol.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data demonstrate the requirement for intact SREBP2 in astrocytes for normal social behavior, memory, and coordinated movement.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Loss of Astrocyte SREBP2 Is Associated with Behavioral Abnormalities.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the latter, in which regulation of cholesterol synthesis is disrupted in both neurons and glia, there is also an increase in VO 2 and activity”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Loss of insulin action in the brain also causes increased phosphorylation of tau protein, an early marker of AD (26).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“this transgene has been shown to be highly expressed in most astrocytes and active as early as E14.5 of gestation (16).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).”
What the sources say
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rather, the reduction in carbohydrate oxidation in muscle, and trends toward reductions in fat and liver, suggest that calories that might normally go to protein synthesis or lipogenesis are being diverted away to the brain, resulting in the smaller tissue weights of these other organs.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In fact, sporadic reports of short-term memory loss associated with statin therapy have prompted the Food and Drug Administration to put a warning on the drug class (35).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal studies followed the National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committees at the Joslin Diabetes Center or the Yale University School of Medicine.”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“and that plaque quantity is not a perfect predictor of disease severity (29,30).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“There is epidemiological evidence that increased serum cholesterol is associated with AD (14)”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At the end of the clamp, relative flux through PDH (V PDH ) and CS (V CS ) pathways in individual tissues was assessed as the ratio of 13 C 2 acetyl CoA to 13 C 3 alanine (i.e., the precursor and product of PDH flux).”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Body Composition and Metabolic Testing. Metabolic cage testing was performed using a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“it is clear that tau phosphorylation itself is not enough to trigger AD”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“Subgroup analysis suggests that ApoE e4 carrier status increases the response to intranasal insulin”
§ Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism > Discussion
What the sources say
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The authors state this as an assumption.
Astrocytes produce most brain cholesterol.
“The brain synthesizes its own cholesterol, presumably in astrocytes.”
“Cholesterol is important for normal brain function and it is believed that astrocytes produce most brain cholesterol.”
The paper relies on this without support.
C6 glioma cells are a valid model for astrocytes in the coculture experiments.
“We cultured GT1-7 mouse hypothalamic cells with C6 rat glioma cells in transwell plates that allow the cells to share nutrients through the media without making physical contact.”
The paper relies on this without support.
hGFAP-cre specifically targets astrocytes and not other cell types.
“we created an astrocyte-specific conditional knockout of SREBP2 by breeding mice expressing hGFAP-cre with mice in which the Srebf2 gene contained lox sites on either side of exon 1.”
The paper relies on this without support.
An increase in RER reflects a shift in substrate oxidation toward carbohydrates.
“This shift in substrate oxidation toward carbohydrates in fed G-SB2KO mice was observed in younger female mice and was confirmed in 9-mo-old male mice as well (Fig. S7B).”
The paper relies on this without support.
Cholesterol is the key mediator of the effect of glial cells on neurite outgrowth.
“consistent with the important factor being cholesterol.”
The paper relies on this without support.
The brain is a near obligate user of carbohydrates for fuel.
“which is already a near obligate user of carbohydrates for fuel.”
The paper relies on this without support.
Cholesterol does not significantly cross the blood-brain barrier.
“however, cholesterol does not significantly cross the blood-brain barrier”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In mice, astrocyte-specific loss of Srebf2 resulted in reduced cholesterol synthesis and defects in neurite outgrowth, behavior, and energy metabolism (58).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [58]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous work identified a direct impairment of neurite outgrowth and synapse formation when cholesterol biosynthesis was disrupted in astrocytes alone, further highlighting the importance of astrocyte health and function in the context of neurodevelopment (Ferris et al., 2017).”
From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Ferris et al., 2017
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Specifically, these receptors promote the apoE-mediated internalization of cholesterol by neurons, an essential process providing lipids to these cells in order to maintain their physiological functions, such as synaptogenesis, neurite outgrowth, and repair of damaged membranes [20].”
From PCSK9 affects astrocyte cholesterol metabolism and reduces neuron cholesterol supplying in vitro: potential implications in Alzheimer’s disease (2022) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, microglia, which are also able to produce apoE (47) and are not impacted by the Cre, are unable to compensate for a lack of astrocyte cholesterol synthesis.”
From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [47]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Interestingly, astrocyte-specific deletion of SREBP2 has been reported to markedly impair brain development, neuronal function, and behavior in mice (Ferris et al., 2017).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Ferris et al., 2017
The cited source says what the claim attributes to it.
In the citing paper
“Mice with SREBP2 knocked out of astrocytes have reduced the production of cholesterol in the astrocytes (47) (SI Appendix, Fig. S4A).”
From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“we have previously demonstrated that overall cholesterol synthesis by neurons increases to compensate for the loss of astrocyte cholesterol (47).”
From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [47]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In fact, reduced striatal DRD2 was consistently demonstrated in patients 45,46,47,48,49 and murine models 27,35,50,51 and its dysregulation is a sensitive measure of HD pathology 37 .”
From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [49]
Experimental — accuracy not yet measured
Citations
Cites
Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., Fuino, R. L., Kawaguchi, K. R., Samoyedny, A. J., Wilson, R. S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59903 · Cited by 1,871
CNS synaptogenesis promoted by glia-derived cholesterol
Mauch, D. H., Nägler, K., Schumacher, S., Göritz, C., Müller, E.-C., Otto, A., & Pfrieger, F. W. (2001) · Science · doi:10.1126/science.294.5545.1354 · Cited by 1,711
Craft, S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.233 · Cited by 1,253
Dietschy, J. M., & Turley, S. D. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r400004-jlr200 · Cited by 1,095
Overview and Findings from the Rush Memory and Aging Project
Bennett, D. A., Schneider, J. A., Buchman, A. S., Barnes, L. L., Boyle, P. A., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322663 · Cited by 849
Bomfim, T. R., Forny‐Germano, L., Sathler, L. B., Brito‐Moreira, J., Houzel, J., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci57256 · Cited by 849
Shimano, H., Horton, J. D., Hammer, R. E., Shimomura, I., Brown, M. S., & Goldstein, J. L. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118951 · Cited by 817
Self-citationPerry, R. J., Camporez, J.-P. G., Kursawe, R., Titchenell, P. M., Zhang, D., Perry, C. J., Jurczak, M. J., Abudukadier, A., Han, M. S., Zhang, X.-M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.012 · Cited by 719
Self-citationRole for neuronal insulin resistance in neurodegenerative diseases
Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D., Kondo, T., Alber, J., Galldiks, N., Küstermann, E., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308724101 · Cited by 659
Self-citationOverview and Findings from the Religious Orders Study
Bennett, D. A., Schneider, J. A., Arvanitakis, Z., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322573 · Cited by 656
Cited by
Sorted by citations
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441
Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
Wang, H., Kulas, J. A., Wang, C., Holtzman, D. M., Ferris, H. A., & Hansen, S. B. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102191118 · Cited by 301
“Astrocyte cholesterol synthesis was disrupted in mice by crossing SREBP2 floxed mice to GFAP-Cre mice, resulting in a homozygous deletion of SREBP2 from astrocytes (47).”
BackgroundMethodResultInfluentialSelf-citationFernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277
Palmer, A. L., & Ousman, S. S. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00337 · Cited by 256
Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
Baloni, P., Funk, C. C., Yan, J., Yurkovich, J. T., Kueider-Paisley, A., Nho, K., Heinken, A., Jia, W., Mahmoudiandehkordi, S., Louie, G., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100138 · Cited by 211
Metadata
- Authors
- Ferris, H. A., Perry, R. J., Moreira, G. V., Shulman, G. I., Horton, J. D., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Yale University (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-01-17
- Volume
- 114
- Issue
- 5
- Pages
- 1189-1194
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5293102
- OpenAlex
- W2579178448
- Semantic Scholar
- 70badba303bcc51b09005182dd47ba9a35088bb7
- Cited by
- 246
- References
- 43
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 34 · 2023: 37 · 2022: 29 · 2021: 25 · 2020: 29 · 2019: 19 · 2018: 5 · 2017: 4
- FWCI
- 15.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (5K08DK097293, R01 DK-40936, MMPC DK059635, R37DK031036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- SREBP2, brain cholesterol, astrocyte-neuron co-culture, neurite outgrowth, brain development, motor defects, energy balance, body composition, glucose oxidation, brain metabolism, diabetes mellitus, metabolic disorders
- MeSH terms
- Animals, Astrocytes, Body Composition, Brain, Cholesterol, Energy Metabolism, Female, Glioma, Glucose, Hyperinsulinism, Male, Mice, Inbred C57BL, Neoplasm Proteins, Nesting Behavior, Oxidation-Reduction, Neurites, Mice, Knockout, Maze Learning, Rotarod Performance Test, Cell Line, Tumor, Mice, Rats, Sterol Regulatory Element Binding Proteins, Sterol Regulatory Element Binding Protein 2, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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