Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation

Abstract

Background & aims: The development and progression of non-alcoholic fatty liver disease are associated with aging, obesity, and type 2 diabetes. Understanding the precise regulatory networks of this process will contribute to novel therapeutic strategies.

Methods: Hepatocyte-specific Men1 knockout mice were generated using Cre/loxP technology. Lipid and glucose metabolic phenotypes and mechanisms were investigated in aging and high-fat diet fed mice.

Results: The expression of menin, encoded by multiple endocrine neoplasia 1 (Men1) gene, is reduced in the liver of aging mice. Hepatocyte-specific deletion of Men1 induces liver steatosis in aging mice. Menin deficiency promotes high-fat diet-induced liver steatosis in mice. Menin recruits SIRT1 to control hepatic CD36 expression and triglyceride accumulation through histone deacetylation.

Conclusions: Our work reveals that the adaptor protein menin is critical for the progression of hepatic steatosis during aging and metabolic imbalance.

Keywords: Aging; HFD; Histone deacetylation; IPGTT; ITT; LMKO; Liver steatosis; MEN1; Menin; NAFLD; SIRT1; Scd-1; TC; TG; high-fat diet; insulin tolerance tests; intra-peritoneal glucose tolerance tests; liver-specific Men1 knockout mice; multiple endocrine neoplasia type 1; non-alcoholic fatty liver disease; stearoyl CoA desaturase-1; total cholesterol; triglyceride.