Soat2 ties cholesterol metabolism to β‐oxidation and glucose tolerance in male mice

Abstract

Background Sterol O‐acyltransferase 2 (Soat2) encodes acyl‐coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride‐rich lipoproteins. Objectives We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. Methods Soat2−/− and wild‐type mice were fed a high‐fat, a high‐carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed. Results Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA‐IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2−/− mice, irrespective of the dietary regimes (2‐way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA‐IR (r = 0.86, p < 0.05), Adipo‐IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very‐low‐density lipoprotein (VLDL)‐TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild‐type mice disappeared in Soat2−/− mice. Genetic depletion of Soat2 also increased whole‐body oxidation by 30% (p < 0.05) compared to wild‐type mice. Conclusion Our data demonstrate that ACAT2‐generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL‐TG) and oxidative (fatty acids) pathways.

A 3D Bioprinted Gut Anaerobic Model for Studying Bacteria–Host Interactions

“…RNAs involved in the apoptotic process such as ATM were increased in Salmonella- infected cells under the anaerobic condition, and RNAs related to cell metabolism, including APOA2 , APOH , and SOAT2 were decreased (Fig. S6 and Table S3 ) [ 42 – 44 ]. KEGG analysis showed enrichment of Ras–proximate-1 (Rap 1) signaling pathway and inflammatory TNF signaling pathway, which mediates cell survival and cell death-inducing signaling (Fig.…”

Combining Dietary Intervention with Metformin Treatment Enhances Non-Alcoholic Steatohepatitis Remission in Mice Fed a High-Fat High-Sucrose Diet

“…For example, patients with hepatocellular carcinoma showed higher plasma concentrations of CE than patients with cirrhosis [ 31 , 32 ]. Indeed, ACAT2-/- (also abbreviated as SOAT2) mice had improved insulin sensitivity, decreased lipid storage, and increased lipid oxidation pathways [ 33 ].…”

ACAT2 as a novel therapeutic target to treat fatty liver disease

“…In a study published in this issue of the Journal of Internal Medicine , Pramfalk et al. fed Soat2 whole‐body knockout mice either a high‐fat or a high‐carbohydrate diet [8]. Under these dietary challenges, Soat2 inactivation induced a dramatic change in lipid and glucose metabolism.…”