The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index; none of the 26 sources its claims cite is checked for support yet.
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.
Overview
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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
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
“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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In the paper
“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 paper
“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.
plaindirectn = 11 ·- Asserted: passes — The authors put it forward as true.
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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
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
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 26
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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
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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.
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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
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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.
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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.
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- Rests on an assumption: hGFAP-cre specifically targets astrocytes and not other cell types.
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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
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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.
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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.
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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.
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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.
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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
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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).”
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BackgroundLipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases
Yang, D., Wang, X., Zhang, L., Fang, Y., Zheng, Q., Liu, X., Yu, W., Chen, S., Ying, J., & Hua, F. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00828-0 · Cited by 179
“Moreover, inactivation of the major transcriptional regulator of the cholesterol synthesis gene SREBP2 in astrocytes results in reduced brain size in mice, particularly in astrocyte-rich regions [34].”
BackgroundAstrocyte Senescence and Alzheimer’s Disease: A Review
Han, X., Zhang, T., Liu, H., Mi, Y., & Gou, X. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00148 · Cited by 177
Brain cell type-specific cholesterol metabolism and implications for learning and memory
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Type I interferon responsive microglia shape cortical development and behavior
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Brain energy metabolism: Astrocytes in neurodegenerative diseases.
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Lipid metabolism in astrocytic structure and function
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A Widespread Neurogenic Potential of Neocortical Astrocytes Is Induced by Injury
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“, Gene Ontology term GO:006695, Cyp4f15, Fdps, and Hmgcs1; Figure 3B), a key function astrocytes undertake to sustain the brain’s metabolic requirements under physiological conditions (Ferris et al., 2017).”
BackgroundCholesterol Biosynthesis and Uptake in Developing Neurons
Genaro-Mattos, T. C., Anderson, A., Allen, L. B., Korade, Z., & Mirnics, K. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00248 · Cited by 117
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The multifaceted role of mitochondria in autism spectrum disorder
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“Previously, a direct link between impairments of synapse formation and neurite outgrowth was found in an astrocyte culture with impaired cholesterol biosynthesis [395].”
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Astroglia-specific contributions to the regulation of synapses, cognition and behaviour
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“Cholesterol levels in astrocytes and glucose metabolism are closely linked (Ferris et al., 2017), A recent 742 Mol.”
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“Disturbances in either the synthesis, transport, or turnover of lipids were shown to trigger synapse loss and neurodegeneration [10, 23, 25, 35, 36].”
BackgroundTargeting fatty acid metabolism in glioblastoma
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“22), glyc-erolipid (e.g., triglycerides), and prenols.”
Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease
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“Therefore, ApoE-mediated cholesterol transport is of critical importance (Jurevics and Morell, 1995; Dietschy and Turley, 2004; Takamori et al., 2006; Czuba et al., 2017; Ferris et al., 2017).”
BackgroundCholesterol Metabolism in Aging and Age-Related Disorders
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“In addition, peripheral lipid metabolism is also severely perturbed in conditional SREBP mutants, but the causing mechanism remains unclear (Ferris et al. 2017).”
BackgroundLipid metabolism, remodelling and intercellular transfer in the CNS
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The role of sleep and wakefulness in myelin plasticity
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“Indeed, mice lacking the ability to syn- thetize lipids in astrocytes display a persistent hypomyelination across neurodevelopment (Camargo et al., 2017; Ferris et al., 2017).”
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“In mice, astrocyte-specific loss of Srebf2 resulted in reduced cholesterol synthesis and defects in neurite outgrowth, behavior, and energy metabolism (47).”
Background24S‐hydroxycholesterol: Cellular effects and variations in brain diseases
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“Among them SREBP-2 is the most abundant in brain tissue (Camargo et al., 2009; DeBose-Boyd & Ye, 2018; Ferris et al., 2017; Horton, 2002).”
BackgroundRegional differences in brain glucose metabolism determined by imaging mass spectrometry
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BackgroundThe shared role of cholesterol in neuronal and peripheral inflammation
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Developmental and extrahepatic physiological functions of SREBP pathway genes in mice
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SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes
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“Interestingly, astrocyte-specific deletion of SREBP2 has been reported to markedly impair brain development, neuronal function, and behavior in mice (Ferris et al., 2017).”
BackgroundCentral nervous system cholesterol metabolism in health and disease
Ho, W. Y., Hartmann, H., & Ling, S. (2022) · IUBMB Life · doi:10.1002/iub.2662 · Cited by 58
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Implications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases
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Mechanisms of astrocyte aging in reactivity and disease
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“Astrocytes enable synaptic function and neuronal activity by physically enmeshing neurons in extracellular matrix components, by supplying neurotrophic and synapto-genic materials, and by transporting membrane components like cholesterol [77–80].”
The translational potential of cholesterol-based therapies for neurological disease
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The Age-dependent Elevation of miR-335-3p Leads to Reduced Cholesterol and Impaired Memory in Brain
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“Consistently, mounting evidence has suggested that cholesterol in general has a beneficial effect on aging or neurodegenerative diseases (Ferris et al., 2017; Martin et al., 2014; Silverman and Schmeidler, 2018).”
MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism
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Cholesterol regulates polymodal sensory transduction in Müller glia
Lakk, M., Yarishkin, O. V., Baumann, J. M., Iuso, A., & Križaj, D. (2017) · Glia · doi:10.1002/glia.23213 · Cited by 49
“Suppression of glioneuronal shuttling of cholesterol through astrocytespecific deletion of SREBP2 causes metabolic defects, altered brain development and abnormal cognition, social and motor behaviors (Ferris et al., 2017).”
BackgroundPapotti, B., Adorni, M. P., Marchi, C., Zimetti, F., Ronda, N., Panighel, G., Lupo, M. G., Vilella, A., Giuliani, D., Ferri, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012192 · Cited by 41
“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].”
BackgroundAstrocyte and oligodendrocyte pathology in Alzheimer's disease
Ziar, R., Tesar, P. J., & Clayton, B. L. L. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00540 · Cited by 47
“In the CNS, astrocytes are a major supplier of lipids, and loss of cholesterol synthesis in astrocytes can disrupt neuronal function [116].”
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The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases
Feringa, F. M., Koppes-den Hertog, S. J., Wang, L. Y., Derks, R. J. E., Kruijff, I., Erlebach, L., Heijneman, J., Miramontes, R., Pömpner, N., Blomberg, N., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01365-z · Cited by 56
“Of the lipid classes that were not measured in the previous mouse study, we found that TGs and free fatty acids (FAs) were most abundant in iMicroglia. iAstrocytes had the highest CE stores, in line with the role of astrocytes as a cholesterol supplier for other brain cell types 49,50 .”
Cholesterol in the CNS: functions, recycling and remyelination
Wuerch, E. C., & Yong, V. W. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03490-8 · Cited by 41
“Additionally, reduced astrocytic cholesterol synthesis in young mice impairs neurodevelopment, leading to behavioural abnormalities, microencepha-lopathy, altered synaptic development, and other deficits [15–17].”
Elastin-Derived Peptides in the Central Nervous System: Friend or Foe
Szychowski, K. A., Skóra, B., & Wójtowicz, A. K. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01140-0 · Cited by 40
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Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference
Song, J. D., Alves, T. C., Befroy, D. E., Perry, R. J., Mason, G. F., Zhang, X., Munk, A., Zhang, Y., Zhang, D., Cline, G. W., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.008 · Cited by 40
“We used [(13)C6] glucose as a tracer during the clamp and used tissue-specific 13C enrichments of alanine and glutamate to measure in vivo VPDH/VCS in soleus and quadriceps muscles (Alves et al., 2011; Ferris et al., 2017; Perry et al., 2018).”
MethodSelf-citationLullau, A. P. M., Haga, E. M. W., Ronold, E. H., & Dwyer, G. E. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1223145 · Cited by 65
“Cholesterol is an integral part of any membrane, and the delivery of astroglial-derived cholesterol to neurons has been reported to be the limiting factor regulating synapse formation (Dietschy and Turley, 2001; Ferris et al., 2017).”
BackgroundThe role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis
White, C. J., Ellis, J. M., & Wolfgang, M. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100830 · Cited by 43
“Astrocytes have previously been characterized as important in other regards of brain lipid metabolism including being the main site of fatty acid oxidation (70) and cholesterol synthesis (71) within the CNS.”
BackgroundUlatowski, L. M., Ghelfi, M. D., West, R., Atkinson, J., Finno, C. J., & Manor, D. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101712 · Cited by 36
“Experimental perturbations to cholesterol transport in the brain were shown to cause impaired development and function of the brain (97, 98).”
BackgroundBalancing cholesterol in the brain: from synthesis to disposal
Qian, L., Chai, A. B., Gelissen, I. C., & Brown, A. J. (2022) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2022.00015 · Cited by 31
“Curiously, mice with a loss of astrocytic SREBP2 display metabolic defects including adiposity reduction and a shift in their metabolism towards carbohydrate oxidation, driven by increased glucose oxidation by the brain [34].”
BackgroundQi, G., Mi, Y., & Yin, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2019.01531 · Cited by 38
Lipid droplet accumulation in microglia and their potential roles
Li, Y., Zhao, Q., Wang, Y., Du, W., Yang, R., Wu, J., & Li, Y. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02633-3 · Cited by 39
“However, astrocytes are absent in the embryonic brain [168, 169].”
Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders
Mitra, S., Banik, A., Saurabh, S., Maulik, M., & Khatri, S. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0998-21.2022 · Cited by 45
“An increase in brain glucose metabolism has been reported after astrocyte-selective knockdown of sterol-regulatory-element-binding protein 2, a receptor-bound transcription factor that regulates genes involved in cholesterol biosynthesis and uptake (Ferris et al., 2017).”
Bai, X., Wu, J., Zhang, M., Xu, Y., Duan, L., Yao, K., Zhang, J., Bo, J., Zhao, Y., Xu, G., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.513605 · Cited by 33
ALS-associated genes in SCA2 mouse spinal cord transcriptomes
Scoles, D. R., Dansithong, W., Pflieger, L. T., Paul, S., Gandelman, M., Figueroa, K. P., Rigo, F., Bennett, C. F., & Pulst, S. M. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa072 · Cited by 33
“Cholesterol cannot pass the blood– brain barrier; thus the brain must synthesize its own which is done in astrocytes, and when cholesterol synthesis is lost, neuronal dysfunction is the result (51).”
The Evolution of Cholesterol-Rich Membrane in Oxygen Adaption: The Respiratory System as a Model
Zuniga-Hertz, J. P., & Patel, H. H. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01340 · Cited by 32
Heterogeneity of Astrocyte Reactivity
Clayton, B. L. L., & Liddelow, S. A. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-031738 · Cited by 33
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“In addition, cholesterol (Ferris et al., 2017) and myo- inositol (Haris et al., 2011) play roles in glial cell function; their increased abundance in the OB during aging may indicate involvement of glial cells.”
BackgroundNg, Y. P., Yip, T. F., Peiris, M. J. S., Ip, N. Y., & Lee, S. M.-Y. (2018) · Journal of NeuroVirology · doi:10.1007/s13365-018-0659-8 · Cited by 27
Zhang, W.-B., Huang, Y. M., Guo, X., Zhang, M.-Q., Yuan, X.-S., & Zu, H. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01593-y · Cited by 35
“However, accumulating data suggests that ferrying the genes that are involved in cholesterol metabolism into mice brain could affect ADrelated pathology and cognitive activity [8, 22, 29, 76].”
BackgroundInsulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes
Geffken, S. J., Moon, S., Smith, C. O., Tang, S. S., Lee, H. H., Lewis, K., Wong, C. W., Huang, Y., Huang, Q., Zhao, Y.-T., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101647 · Cited by 27
“Loss of cholesterol synthesis in astrocytes impairs normal brain development while also inducing cognitive dysfunction in mice [61].”
BackgroundCholesterol Metabolism in Neurodegenerative Diseases
He, K., Zhao, Z., Zhang, J., Li, D., Wang, S., & Liu, Q. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0674 · Cited by 30
“Loss of astrocytic SREBP2 functionally impairs neuronal dendrite outgrowth in vivo cocultures (Ferris et al., 2017), further emphasizing the necessity of astrocyte-derived cholesterol in maintaining normal neuronal function.”
Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective
Shang, G., Shao, Q., Lv, K., Xu, W., Ji, J., Fan, S., Kang, X., Cheng, F., Wang, X., & Wang, Q. (2024) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01217-3 · Cited by 24
Function and therapeutic value of astrocytes in diabetic cognitive impairment
Meng, F., Fu, J., Zhang, L., Guo, M., Zhuang, P., Yin, Q., & Zhang, Y. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105591 · Cited by 26
Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline
Anderson, T., Sharma, S. K., Kelberman, M. A., Ware, C. B., Guo, N., Qin, Z. S., Weinshenker, D., & Parent, M. B. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15900 · Cited by 26
“Astrocytes supply much of the brain's required cholesterol (Björkhem & Meaney, 2004 ; Ferris et al., 2017; Zhang & Liu, 2015 ), yet astrocytes were notably absent from our cell-type deconvolu - tion results.”
BackgroundDefects of Nutrient Signaling and Autophagy in Neurodegeneration
Ondaro, J., Hernández-Eguiazu, H., Garciandia-Arcelus, M., Loera‐Valencia, R., Rodríguez-Gómez, L., Jiménez-Zúñiga, A., Goikolea, J., Rodriguez‐Rodriguez, P., Ruiz‐Martínez, J., Moreno, F., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.836196 · Cited by 28
“When cholesterol synthesis disruption causes neuronal function impairment, showing behavioral defects in mice (Ferris et al., 2017).”
BackgroundLorenzo, P. I., Vázquez, E. M., López–Noriega, L., Fuente-Martín, E., Mellado‐Gil, J. M., Franco, J. M., Cobo‐Vuilleumier, N., Guerrero-Martinez, J. A., Romero‐Zerbo, S., Pérez-Cabello, J. A., et al. (2021) · Theranostics · doi:10.7150/thno.57237 · Cited by 27
“Similarly, astrocytic expression of SREBF2 the central transcription factor coordinating the expression of cholesterol biosynthesis genes as well as SLC1A2 a glutamate transporter were shown to be essential for neuronal function an viability [51-53].”
BackgroundCantando, I., Centofanti, C., D’Alessandro, G., Limatola, C., & Bezzi, P. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1354259 · Cited by 27
Sugiyama, T., Murao, N., Kadowaki, H., Takao, K., Miyakawa, T., Matsushita, Y., Katagiri, T., Futatsugi, A., Shinmyo, Y., Kawasaki, H., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102758 · Cited by 23
Birolini, G., Valenza, M., Di Paolo, E., Vezzoli, E., Talpo, F., Maniezzi, C., Caccia, C., Leoni, V., Taroni, F., Bocchi, V. D., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012519 · Cited by 27
“…SREBP2 with a neuronal or an astrocytic marker (NeuN and GFAP, respectively), we found that the increased nuclear localization of SREBP2 was specific for glial cells (Fig 4J and K), the major producers of cholesterol in the adult brain (Mauch et al, 2001; Camargo et al, 2012; Ferris et al, 2017).”
BackgroundAPOE ε 4 and resting‐state functional connectivity in racially/ethnically diverse older adults
Turney, I. C., Chesebro, A. G., Rentería, M. A., Lao, P. J., Beato, J. M., Schupf, N., Mayeux, R. P., Manly, J. J., & Brickman, A. M. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12094 · Cited by 25
Astrocyte involvement in metabolic regulation and disease
Naveed, M., Smedlund, K., Zhou, Q.-G., Cai, W., & Hill, J. W. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.08.001 · Cited by 22
Bridging metabolic syndrome and cognitive dysfunction: role of astrocytes
Li, Z., Jiang, Y., Long, C., Peng, X., Tao, J., Pu, Y., & Yue, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1393253 · Cited by 22
Cleland, N. R. W., & Bruce, K. D. (2022) · Biochimie · doi:10.1016/j.biochi.2022.08.012 · Cited by 23
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04672-w · Cited by 19
“This is reduced with SREBP2 knockdown astrocytes; it also shows that mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor deficits [150].”
Gonzalez, L., & Bezzi, P. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70092 · Cited by 24
Incretin-based therapeutics for the treatment of neurodegenerative diseases
Vear, A., Heneka, M. T., & Clemmensen, C. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01263-4 · Cited by 25
“https://doi.org/10.1038/s42255-025-01263-4 glucose sensing in the CNS and systemic glucose metabolism 50 , and is the main regulator of cholesterol synthesis in the brain 51 .”
InfluentialLange, J., Gillham, O., Flower, M. D., Ging, H., Eaton, S. D., Kapadia, S., Neueder, A., Duchen, M. R., Ferretti, P., & Tabrizi, S. J. (2023) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2023.102448 · Cited by 23
“Human HD astrocytes derived from PSC (pluripotent stem cells), such as embryonic (ESC) or induced pluripotent stem cell (iPSC), have been shown to mirror some phenotypes observed in post-mortem human HD brains, but have yet to be extensively studied (Cho et al., 2019; Garcia et al., 2019).”
BackgroundResultInfluentialAlavi, M. S., Karimi, G., Ghanimi, H. A., & Roohbakhsh, A. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175726 · Cited by 25
The Memory Orchestra: Contribution of Astrocytes
Chen, Y., Jin, S., Yang, J., & Gao, T. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01024-x · Cited by 24
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
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