Soat2-KO Mouse

Soat2, also known as sterol O-acyltransferase 2, encodes acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2). This enzyme is crucial for synthesizing cholesteryl esters in hepatocytes and enterocytes, which are either stored or secreted into nascent triglyceride-rich lipoproteins, thus playing a significant role in cholesterol metabolism [1,3,4].

Genetic depletion of Soat2 in mice has revealed its multiple functions. In male mice, Soat2-/-mice showed improved glucose, insulin, HOMA-IR, OGTT, and insulin tolerance test results regardless of diet, along with a 30% increase in whole-body oxidation. The positive correlations between various lipid and glucose metabolism parameters in wild-type mice disappeared in Soat2-/-mice, indicating that ACAT2-generated cholesteryl esters negatively affect metabolic control by retaining TG in the liver, and genetic inhibition of Soat2 improves liver steatosis by partitioning lipids into secretory and oxidative pathways [1]. In female mice, Soat2-/-mice fed high-fat or high-carbohydrate, low-cholesterol diets had less hepatic steatosis, decreased expression of genes involved in de novo lipogenesis, and lower hepatic GLUT2 [3]. In intestine-specific Soat2 knockout (Soat2I-KO) mice, the development of dietary-induced obesity was prevented due to reduced intestinal lipid absorption [2]. In lysosomal acid lipase-deficient mice, loss of Soat2 function led to less hepatomegaly, reduced sequestration of esterified cholesterol, decreased liver transaminase activities, and lower hepatic mRNA expression levels for markers of inflammation, as well as curtailed esterified cholesterol entrapment in the small intestine [5].

In conclusion, Soat2 is essential for cholesterol metabolism and cholesteryl ester synthesis. Gene knockout mouse models have shown that Soat2 plays a role in metabolic control, hepatic steatosis, obesity, and the progression of lysosomal acid lipase-deficiency-related diseases. Understanding Soat2's function through these models provides insights into the mechanisms of related diseases and potential therapeutic targets.

References:

1. Pramfalk, Camilla, Ahmed, Osman, Pedrelli, Matteo, Eriksson, Mats, Parini, Paolo. 2022. Soat2 ties cholesterol metabolism to β-oxidation and glucose tolerance in male mice. In Journal of internal medicine, 292, 296-307. doi:10.1111/joim.13450. https://pubmed.ncbi.nlm.nih.gov/34982494/

2. Liang, Jingjia, Shao, Wentao, Ni, Pu, Jiang, Zhaoyan, Gu, Aihua. 2024. siRNA/CS-PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403442. doi:10.1002/advs.202403442. https://pubmed.ncbi.nlm.nih.gov/39297413/

3. Ahmed, O, Pramfalk, C, Pedrelli, M, Eriksson, M, Parini, P. 2018. Genetic depletion of Soat2 diminishes hepatic steatosis via genes regulating de novo lipogenesis and by GLUT2 protein in female mice. In Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 51, 1016-1022. doi:10.1016/j.dld.2018.12.007. https://pubmed.ncbi.nlm.nih.gov/30630736/

4. Pavanello, Chiara, Ossoli, Alice, Strazzella, Arianna, Parini, Paolo, Calabresi, Laura. 2022. Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans. In Journal of lipid research, 63, 100232. doi:10.1016/j.jlr.2022.100232. https://pubmed.ncbi.nlm.nih.gov/35598637/

5. Lopez, Adam M, Chuang, Jen-Chieh, Turley, Stephen D. 2017. Impact of loss of SOAT2 function on disease progression in the lysosomal acid lipase-deficient mouse. In Steroids, 130, 7-14. doi:10.1016/j.steroids.2017.11.015. https://pubmed.ncbi.nlm.nih.gov/29246491/