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Soat2 ties cholesterol metabolism to beta-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.
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Submitted on : Tuesday, May 24, 2022 - 3:15:18 PM
Last modification on : Thursday, May 26, 2022 - 3:13:51 AM

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Camilla Pramfalk, Osman Ahmed, Matteo Pedrelli, Mirko E. Minniti, Serge Luquet, et al.. Soat2 ties cholesterol metabolism to beta-oxidation and glucose tolerance in male mice. Journal of Internal Medicine, Wiley, 2022, ⟨10.1111/joim.13450⟩. ⟨hal-03677210⟩

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