• J. Intern. Med. · Aug 2022

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

    • Camilla Pramfalk, Osman Ahmed, Matteo Pedrelli, Mirko E Minniti, Serge Luquet, Raphaël Gp Denis, Maria Olin, Jennifer Härdfeldt, Lise-Lotte Vedin, Knut R Steffensen, Mikael Rydén, Leanne Hodson, Mats Eriksson, and Paolo Parini.
    • Cardio Metabolic Unit, Department of Medicine and Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    • J. Intern. Med. 2022 Aug 1; 292 (2): 296307296-307.

    BackgroundSterol 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.ObjectivesWe aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice.MethodsSoat2-/- 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.ResultsGlucose, 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.ConclusionOur 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.© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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