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
Cites
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CNS synaptogenesis promoted by glia-derived cholesterol
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Overview and Findings from the Rush Memory and Aging Project
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Self-citationRole for neuronal insulin resistance in neurodegenerative diseases
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Self-citationOverview and Findings from the Religious Orders Study
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Cited by
Sorted by citations
Items 101–200 of 204
Fernández‐Gayol, O., Sanchís, P., Aguilar, K., Navarro‐Sempere, A., Comes, G., Molinero, A., Giralt, M., & Hidalgo, J. (2019) · Neuroendocrinology · doi:10.1159/000496845 · Cited by 15
Freel, B. A., Kelvington, B. A., Sengupta, S., Mukherjee, M., & Francis, K. R. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049843 · Cited by 17
“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).”
N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis
Ozkan, T., Grzesik, D., Romano, L. E. L., Chapple, J. P., King, P., & Shoulders, C. C. (2024) · Cells · doi:10.3390/cells13151255 · Cited by 19
“…of the processes regulating hepatic de novo cholesterol synthesis, including those mediated by sterol regulatory element-binding protein (SREBP) 2, is predominantly extrapolated from studies performed in extrahepatic cells [20–25] that do not model key aspects of the hepatocyte’s functions.”
BackgroundFeringa, F. M., Hertog, S. K.-D., Wang, L. Y., Derks, R. J. E., Kruijff, I. D., Erlebach, L., Heijneman, J., Miramontes, R., Pömpner, N., Blomberg, N., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.01.601474 · Cited by 21
“Astrocytes had the highest cholesterol ester (CE) stores, in line with the role of astrocytes as cholesterol supplier for other brain cell types 45,46 .”
BackgroundPotential role of Bcl2 in lipid metabolism and synaptic dysfunction of age-related hearing loss
Liu, Y., Zhang, H., Fan, C., Liu, F., Li, S., Li, J., Zhao, H., & Zeng, X. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106320 · Cited by 19
“…in the central nervous system for synaptic and dendrite formation, as well as its involvement in axon guidance and participation as a precursor in various biosynthetic pathways (Barres and Smith, 2001; Ferris et al., 2017; Fünfschilling et al., 2012; Korade and Kenworthy, 2008; X. Li et al., 2021).”
BackgroundThe contribution of astrocytes to obesity-associated metabolic disturbances
Obara‐Michlewska, M. (2022) · Journal of Biomedical Research · doi:10.7555/jbr.36.20200020 · Cited by 20
Singh, K., Cornell, C. S., Jackson, R., Kabiri, M., Phipps, M., Desai, M., Fogle, R., Ying, X., Anarat‐Cappillino, G., Geller, S., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-86663-8 · Cited by 19
Szychowski, K. A., & Gmiński, J. (2019) · Cytokine · doi:10.1016/j.cyto.2019.154930 · Cited by 19
Zhu, Z., Hu, Y., Zhou, Y., Zhang, Y., Yu, L., Tao, L., Guo, A., & Fang, Q. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.04.022 · Cited by 17
Dissecting the Brain/Islet Axis in Metabesity
Fuente-Martín, E., Mellado‐Gil, J. M., Cobo‐Vuilleumier, N., Martín‐Montalvo, A., Romero‐Zerbo, S., Contreras, I. D., Hmadcha, A., Soria, B., Bermudo, F. M., Reyes, J. C., et al. (2019) · Genes · doi:10.3390/genes10050350 · Cited by 17
“Moreover, the disruption of astrocytic cholesterol synthesis alters brain development and function and results in systemic metabolic defects affecting carbohydrate and lipid oxidation at the whole-body level [142].”
BackgroundLipids in major depressive disorder: new kids on the block or old friends revisited?
van der Heijden, A. R., & Houben, T. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1213011 · Cited by 15
“As cholesterol is indispensable for neurons (63), astrocytes (64) and microglia (65), these CNS cells synthesize cholesterol in situ via the Bloch or Kandutsch-Russel pathway [also see (32)].”
BackgroundXu, S.-F., Pang, Z.-Q., Fan, Y.-G., Zhang, Y.-H., Meng, Y., Bai, C.-Y., Jia, M., Chen, Y.-H., Wang, Z.-Y., & Guo, C. (2022) · Glia · doi:10.1002/glia.24259 · Cited by 15
Na, S., Duan, X., Wang, R., Fan, Y., Xue, K., Tian, S., Yang, Z., Li, K., & Yue, J. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01758-7 · Cited by 17
Zhu, S., Wang, Y., Li, Y., Li, N., Zheng, Y., Li, Q., Guo, H., Sun, J., Zhai, Q., & Wang, Q. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1499591 · Cited by 14
“Studies have shown that disruption of the astrocytic cholesterol synthesis pathway can lead to axonal growth restriction, synaptic damage, and learning and memory impairment (Ferris et al., 2017; Xu et al., 2022).”
InfluentialYuan, Z., Pavel, M. A., & Hansen, S. B. (2025) · Communications Biology · doi:10.1038/s42003-025-08026-7 · Cited by 14
“The knockout leads to a reduction in cholesterol production, affecting the primary source of cholesterol for neurons 9,55 .”
Hu, Z., Yuan, Y.-Q., Tong, Z., Liao, M., Yuan, S., Wu, W., Tang, Y., Wang, Y., Tang, C., & Liu, W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612847 · Cited by 18
“Extensive research has demonstrated that the depletion of cholesterol in the brain critically contributes to the pathogenesis of AD and is hypothesized to be closely linked to cognitive deterioration [3,4].”
BackgroundZhang, J., Zhang, F.-R., Wu, J., Li, J., Yang, Z.-Q., & Yue, J. (2020) · Toxicology · doi:10.1016/j.tox.2020.152381 · Cited by 13
Laue, K., Pozzi, S., Zerbib, J., Bertolio, R., Eliezer, Y., Cohen‐Sharir, Y., Winkler, T., Caputo, M., Ricci, A. A., Adler, L. N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02446-1 · Cited by 23
“…(100,000 cells) of each genotype ( TP53 -WT, TP53 -mut/ TP53 -WT, TP53 -mut/ TP53 -del17p, TP53 -mut/ TP53 -KO) were plated in triplicate in 2-cm wells with Lonza MEBM (CC-3151) and MEGM SingleQuots (CC-4136) and cultured for 72 h, with media refreshed 2 h before collection (Supplementary Note 42).”
Triplet, E. M., Kim, H. N., Yoon, H., Radulovic, M., Kleppe, L. S., Simon, W. L., Choi, C., Walsh, P., Dutton, J. R., & Scarisbrick, I. A. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105294 · Cited by 12
Hasdianty, A., Suhaila, Y. N., Hazwan, A., Maniyam, M., Fadzli, A., & Ibrahim, A. L. (2020) · doi:10.1016/j.bcab.2020.101840 · Cited by 12
Cholesterol Sulfate: Pathophysiological Implications and Potential Therapeutics
Yu, X., Lei, S., Shen, Y., Liu, T., Li, J., Wang, J., & Su, Z. (2025) · Biomolecules · doi:10.3390/biom15050646 · Cited by 14
“This not only ensures the structural stability of these cells but also supports neuronal development [134].”
Camdzic, M., Aga, D. S., & Atilla‐Gokcumen, G. E. (2023) · Environment & Health · doi:10.1021/envhealth.3c00022 · Cited by 16
Wang, S., Lu, A.-X., Li, W.-H., Zhang, H., Hu, C., Liu, J., Pan, H., Wu, M., Xu, X., Yan, C., et al. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.115026 · Cited by 11
Ectopic fat accumulation in human astrocytes impairs insulin action
Heni, M., Eckstein, S. S., Schittenhelm, J., Böhm, A., Hogrefe, N., Irmler, M., Beckers, J., de Angelis, M. H., Häring, H., Fritsche, A., et al. (2020) · Royal Society Open Science · doi:10.1098/rsos.200701 · Cited by 14
Baloni, P., Funk, C. C., Yan, J., Yurkovich, J. T., Kueider‐Paisley, A., Nho, K. T., Heinken, A., Jia, W. P., MahmoudianDehkordi, S., Louie, G., et al. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3596216 · Cited by 13
Goncharov, N., Terpilowski, M., Shmurak, V., Belinskaya, D., & Avdonin, P. (2019) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093019020042 · Cited by 11
Regulation of neuroinflammation by astrocyte-derived cholesterolPreprint
Wang, H., Kulas, J. A., Yu, Y., Milstein, J. L., Peng, C. E., Higginbotham, H., Christensen, J. R., Kovacs, M. A., Schüle, A. M., Oliinyk, D., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.12.520161 · Cited by 10
“SREBP2 flox/flox mice (a generous gift of Dr. Jay Horton at UT Southwestern, now available through Jackson labs) were crossed to the hGFAP-Cre as previously described 24 .”
Self-citationŽagare, A., Sauter, T., Barmpa, K., Pacheco, M. P., Krüger, R., Schwamborn, J. C., & Saraiva, C. (2025) · npj Systems Biology and Applications · doi:10.1038/s41540-025-00509-x · Cited by 8
“Brain cholesterol synthesis occurs in situ predominantly by astrocytes since it cannot cross the blood-brain barrier 55 .”
Rubio, S., Somers, V., & Fraussen, J. (2024) · European Journal of Immunology · doi:10.1002/eji.202451333 · Cited by 10
“MIF has been shown to have an effect on cholesterol homeostasis, which is mainly regulated by astrocytes in the CNS [68].”
Nam, Y. R., Kang, M., Kim, M., Seok, M. J., Yang, Y., Han, Y. E., Oh, S., Kim, D. G., Son, H., Chang, M., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.03.012 · Cited by 10
“The capacity for cholesterol synthesis is regarded as a characteristic of young and healthy astrocytes with potent neurotrophic potential [32,33].”
Astrocyte signaling and interactions in Multiple Sclerosis
Ortiz, C. K. C., & Eroğlu, Ç. (2023) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2023.102307 · Cited by 12
Ensemble Estimation of Generalized Mutual Information With Applications to Genomics
Moon, K. R., Sricharan, K., & Hero, A. O. (2021) · IEEE Transactions on Information Theory · doi:10.1109/tit.2021.3100108 · Cited by 11
“…in the brain [98], SEPT6 has been found to be important for the developing neural tube in zebra fish [99], SREBF2 is necessary for normal brain development in mice [100], NR2E1 is predominantly expressed in the developing brain [101], and ZNF804A may help regulate early brain development [102].”
BackgroundValenza, M. (2025) · Journal of Huntington s Disease · doi:10.1177/18796397251336192 · Cited by 9
“59 Moreover, in PET imaging studies, progressive striatal and cortical glucose hypometabolism has been observed in HD patients, 76 – 78 and GLUT1 expression is reduced in cortical tissues and fi broblasts from pediatric HD patients.”
Immune cells in Alzheimer’s disease: insights into pathogenesis and potential therapeutic targets
Fu, X., Cai, H., Quan, S., Ren, Z., Xu, Y., & Jia, L. (2024) · Medical Review · doi:10.1515/mr-2024-0064 · Cited by 10
“Its levels are largely una ff ected by dietary intake, owingto the presence of the BBB. Astrocytes express sterol regulatory element-binding protein 2 (SREBP2) and APOE on their surfaces, facilitating cholesterol synthesis and transport [114].”
Li, J., Long, S., Zhang, Y., Wei, W., Yu, S., Liu, Q., Hui, X., Li, X., & Wang, Y. (2024) · MedComm · doi:10.1002/mco2.754 · Cited by 8
“16,17 The interaction between astrocytes and the resident or infiltrating cells of the CNS plays a significant role in tissue physiology and pathology.”
BackgroundWang, S., Xu, X., Lu, A.-X., Li, W.-H., Liu, J., Liu, C., & Yan, C. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.114307 · Cited by 11
Zubillaga, M., Rosa, D. E., Astiz, M., Tricerri, M. A., & Arnal, N. (2022) · ACS Omega · doi:10.1021/acsomega.2c00703 · Cited by 9
Ganesan, D., Santhaseela, A. R., Rajasekaran, S., Selvam, S., & Jayavelu, T. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.14979 · Cited by 11
Astrocytes as Therapeutic Targets in Neurodegenerative Disorders
Salas, I. H., Alfonso-Triguero, M., Castro, B. D., Elazar, N., Escartin, C., Akl, C. F., Hill, S. A., Quintana, F. J., & Arranz, A. M. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.1379-25.2025 · Cited by 10
Molecular Mechanisms of Astrocyte Involvement in Synaptogenesis and Brain Synaptic Plasticity
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Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis
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“This phenomenon is supported by the existence of SREBP2 in ER, wherein the presence of higher SREBP2 precursors (a kind of cholesterol) remains sequestered by SCAP (SREBP cleavage activating protein) [217].”
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Srebf2 mediates successful optic nerve axon regeneration via the mevalonate synthesis pathway
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BackgroundSIRT-1 Activity Sustains Cholesterol Synthesis in the Brain
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“Previous work has shown that astrocytes are also producers of cholesterol and neurons are recipients (Pfrieger & Ungerer, 2011; Valenza et al, 2015; Ferris et al, 2017), again highlighting the importance of lipid exchange between cell types in the brain.”
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Emerging roles of astrocytes in hippocampal circuitry and behavior
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“Inferior frontal gyrus (IFG) Mount Sinai Brain Bank (MSBB) 230 Ribo-zero AD (95), Normal (65), Possible AD (36), Probable AD (34) Male (79), Female (151) Ɛ2/Ɛ2 (2), Ɛ2/Ɛ3 (15), Ɛ2/Ɛ4 (1), Ɛ3/Ɛ3 (77), Ɛ3/Ɛ4 (41), Ɛ4/Ɛ4 (3), NA (91)”
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Sleep loss induces cholesterol-associated myelin dysfunction
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“Astrocytes are recognized as the primary source of cholesterol in the brain (56), and microglia can also contribute, particularly following demyelination (57).”
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“Astrocyte specific SREBP2 knockout mice exhibit impaired neural development and systemic metabolic deficits [38], both of which are present in SLOS patients.”
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“In agreement with previous works, the elevation in SREBP-2 coincided with the increase in HMGCR expression [49, 52], and this elevation was once again more pronounced in female than in male astrocytes.”
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“At all stages throughout the life and particularly in the adulthood, astrocytes are a major source of cholesterol to neurons so as to support their normal development and functions [27].”
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“Pathways enriched in Cluster 4 indicate that gene expression changes could be associated with reduced lipid synthesis, transport, and cell activity in aging astrocytes (Allende et al. 2024; Ferris et al. 2017; Lee et al. 2021) (Figure 4L).”
Astrocytic lipid dysregulation as an early driver of neurodegeneration
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“Consistent with these findings, evidence from human post-mortem tissue and animal models indicates that astrocytic cholesterol handling is disrupted at early stages of AD 10,14,16 .”
Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
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Biallelic variants in SREBF2 cause autosomal recessive spastic paraplegia.
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“The depletion of cholesterol from astrocytes was achieved by targeting sterol regulatory element-binding protein 2 (SREBP2), a crucial regulator of cholesterol synthesis ( Ferris et al., 2017 ; Wang et al., 2021 ).”
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“Consistent with this, cholesterol biosynthesis pathways were reduced, aligning with studies showing that impaired astrocytic cholesterol synthesis can impact neuronal function and contribute to disease progression [73].”
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“SREBF2 is the major transcription factor regulating the cholesterol synthesis pathway 52 , and its loss in astrocytes alters mouse brain development and behavior 53 .”
Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice
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“128 The DHA-induced increased expression of cholesterol synthesis genes in astrocytes suggests that restoration of astrocyte cholesterol homeostasis, which is crucial for neuronal function, 57 microglia support, 58 and A β clearance, 59–61 plays a role in AD amelioration.”
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Astrocytes in Multiple Sclerosis: Getting to the Core
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A dual role for cGAS in shaping cellular and organismal responses to genomic instabilityPreprint
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“…were also associated with reactive astrogliosis and neuroinflammatory states ( insig , nfil3 , and aqp4 ) (Kobayashi et al. 2011; Xiao and Hu 2014; Ferris et al. 2017), cGAS – STING and interferon signaling ( insig ) (Wang et al. 2014), neuronal growth and function ( rtn4/nogo and gas7 ) (Lee et…”
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“Astrocytes, the most abundant type of glial cells in the central nervous system (CNS), exhibit complex morphology (16,17).”
Astrocytic Cholesterol Fine-Tunes the Balance of Different Modes of Synaptic Exo- and EndocytosisPreprint
Myeong, J., & Klyachko, V. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.28.696787
“Many disease states result in decreased brain cholesterol synthesis, for example in diabetes this occurs due to a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription (58).”
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Potential of Natural Products in the Treatment of Glioma: Focus on Molecular Mechanisms
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A Lipid Rafts Theory of Alzheimer's Disease
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“70,108 Cholesterol stimulates Abeta production, yielding two types of neurons associated with chronic cholesterol in AD.”
BackgroundToral-Ríos, D., Long, J. M., Ulrich, J. D., Yu, J., Strickland, M. R., Han, X., Holtzman, D. M., Cashikar, A. G., & Paul, S. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.08.556884
“Interestingly, astrocyte-specific deletion of SREBP2 has been reported to markedly impair brain development, neuronal function, and behavior in mice (61).”
BackgroundGopalan, A. B., van Uden, L., Sprenger, R. R., Marx, N. F.-N., Bogetofte, H., Neveu, P. A., Meyer, M., Noh, K., Diz-Muñoz, A., & Ejsing, C. S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.31.505694 · Cited by 2
“Previous work has shown that astrocytes are producers of cholesterol and neurons are recipients (Pfrieger & Ungerer, 2011; Valenza et al., 2015; Ferris et al., 2017), again highlighting the importance of lipid exchange between cell types in the brain.”
BackgroundBlood-Brain Barrier Therapeutics for Neurological Diseases
Sahni, A., & Katchur, N. J. (2021) · Journal of Student Research · doi:10.47611/jsrhs.v10i3.1735
Lorenzo, P. I., Fuente-Martín, E., Mellado‐Gil, J. M., Guerrero-Martinez, J. A., Cobo‐Vuilleumier, N., Comaills, V., Vázquez, E. M., Romero‐Zerbo, S., Franco, J. M., Pérez-Cabello, J. A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.15.431213
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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