8359 Increased hepatic SGK1 activity promotes metabolic dysfunction-associated fatty liver disease in a sex-dependent manner

Abstract Disclosure: A. Vastola-Mascolo: None. G. Hernández: None. D. Alvarez de la Rosa: None. The serum and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr kinase with key roles in fluid and electrolyte homeostasis, blood pressure regulation and energy metabolism. Its expression is controlled by steroid hormones such as glucocorticoids, mineralocorticoids and estrogen, in addition to other stimuli such as glucose. SGK1 activation mainly depends on the PI3 kinase pathway, implicating it in insulin signaling. Previous work from our laboratory demonstrated that a systemic increase in SGK1 activity exacerbates diet-induced development of metabolic syndrome in mouse, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, a high-fat diet rapidly led to the development of hepatic steatosis. We now test the hypothesis that at least part of the effects of increased systemic SGK1 activity promoting the development of metabolic syndrome are due to alterations in liver glucose or lipid handling. To that end we developed a mouse strain with hepatocyte-specific transgenic SKG1 expression and challenged it with high-fat or high-fat/high-sucrose diets. Our results show sex differences in the development of obesity, with a marked increase in body weight in female, but not male transgenic animals. Glucose homeostasis was normal in both sexes. Increased obesity in females correlated with increased lipid accumulation in the liver. However, liver fibrosis, inflammation and dyslipidemia were more marked in male animals, further suggesting an interaction between SGK1 and sex steroid hormone signaling. Our results demonstrate a key role of SGK1 in liver lipid metabolism and suggest a crosstalk between this signaling pathway and sex hormones, which determine a more negative outcome in male animals. Presentation: 6/1/2024