Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver‐mesenteric adipose tissue fatty acid mobilization
Bibliographic record
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is escalating paralleled with obesity rates in both adults and children. Mammalian sirtuin 1 (SIRT1), a highly conserved NAD + ‐dependent protein deacetylase, has been identified as a metabolic regulator of lipid homeostasis and a potential target for NAFLD prevention and treatment. However, the mechanism of how SIRT1, in particularly its deacetylase activity, affects NAFLD has not been well investigated. The current investigation addressed the causal effect of systemic SIRT1 activity on NAFLD development and the potential mechanism involved in both liver and mesenteric adipose tissue. At 6 weeks of age, both SIRT1 homozygous mice carrying a point mutation (H355Y, SIRT1 Y/Y , n=10) that ablates the catalytic activity and their corresponding wild type littermates (WT, n=10) were fed with high fat diet (HFD, 60% calories from fat) for 34 weeks. Results showed no changes of body weight, liver weight and body composition (anlyzed by EchoMRI‐700) between WT and SIRT1 Y/Y mice, but SIRT1 Y/Y mice showed significantly higher level of hepatic triglyceride, and a trend of more severe hepatic steatosis by pathological analysis, which was accompanied with higher protein levels of LXRα, SREBP‐1, SCD1, involved in lipogenesis, and decreased phosphorylation of LKB1 and AMPK in the liver. In the mesenteric adipose tissue, mRNA expression of lipogenic genes ( lxrα , srebp‐1c , scd1 and fas ) increased significantly in SIRT1 Y/Y mice, as compared with those of wild‐type mice. Fatty acid oxidation biomarkers ( acox1 , acox3 , cpt , ucp1 , sirt3 ) in both liver and mesenteric adipose tissue were comparable between groups. Interestingly, we observed that in SIRT1 Y/Y mice, the mRNA level of hormone sensitive lipase ( hsl ), adipose triglyceride lipase ( atgl ) and perilipin‐2 , involved in lipolysis, significantly increased in mesenteric adipose tissue (not in epididymal adipose tissue), as compared with those of WT. These changes were correlated with higher circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. Taken together, the present study provided novel experimental evidence that under HFD‐induced metabolic surplus, the lack of SIRT1 catalytic activity promoted release of FFA from mesenteric fat into systemic circulation and escalated NAFLD by interfering with lipid homeostasis in both liver and mesenteric adipose tissue. Support or Funding Information Supported by USDA/NIFA (2015‐67017) and USDA/ARS (58‐1950‐0014)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".