Mechanisms Underlying the Modulation of Hepatic Lipid and Lipoprotein Metabolism in Insulin Resistant States: Examining the Contribution of the Gut and Adipose Tissue
Bibliographic record
Abstract
Dyslipidemia and non-alcoholic fatty liver disease (NAFLD) are complications of insulin resistant states and are primarily caused by alterations in hepatic very low density lipoprotein (VLDL) production. Recent research has implicated a gut-liver-adipose tissue axis involving bile acids and the gut microbiota, as well as adipose tissue secreted hormones and miRNAs in the modulation of hepatic lipid and lipoprotein homeostasis. Bile acid signalling through the Takeda G protein coupled receptor 5 (TGR5) and the gut microbiota have been shown to alter intestinal glucagon-like peptide 1 (GLP-1) production, which has independently been shown to modulate hepatic lipoprotein metabolism. Additionally, adipose tissue expression of neuregulin 4 (Nrg4) has been shown to be altered following BAT activation, and miR-130b has been shown to be altered in obesity. Both Nrg4 and miR-130b been shown to independently modulate hepatic lipoprotein secretion. Therefore, I hypothesize that TGR5 signalling and the gut microbiota exert modulatory effects which may reduce hepatic excursion of VLDL through a GLP1 receptor (GLP-1R) dependent pathway. Further, I propose that alterations in Nrg4 expression observed following BAT activation, and alterations in miR-130b expression in obesity independently modulate hepatic lipid homeostasis. To investigate bile acid mediated regulation of hepatic lipoprotein metabolism, we developed a novel TGR5 knockout (KO) hamster model and characterized the model in normal and insulin resistant states. Subsequently employing both TGR5 KO and GLP-1R KO hamsters, we demonstrated that bile acids can acutely decrease hepatic VLDL secretion, an effect that was dependent on vagal GLP-1R signalling. To assess the involvement of the gut microbiota, we performed antibiotic induced microbiota depletion (AIMD) in hamsters and observed perturbations in hepatic lipid storage and secretion. We next examined the effects of Nrg4 and miR-130b in isolated hepatocytes and in animal models. Both Nrg4 administration and miR-130b overexpression were associated with increased hepatic VLDL secretion. Taken together, data presented in this thesis demonstrates the importance of gut and adipose tissue signalling in the modulation of hepatic lipid accumulation and VLDL production. Modulating these pathways in vivo may be a potential therapeutic approach to correct the dyslipidemia and NAFLD commonly associated with the metabolic syndrome.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".