Abstract 524: Role of Transmembrane Protein 55B in Insulin Signaling and Hepatic Lipid Metabolism
Hepatic steatosis is the leading cause of liver disease in the United States and is associated with increased risk of cardiovascular disease. Insulin resistance appears to be a major determinant of hepatic steatosis, as improper hepatic insulin signaling stimulates lipogenesis and dysregulates lipoprotein secretion, resulting in fat accumulation in the liver. Insulin signal transduction is dependent on phosphatidylinositol-4,5-biphosphate (PIP2) conversion to phosphatidylinositol-3,4,5-biphosphate (PIP3), which results in activation of AKT. Transmembrane protein 55B (TMEM55B), a gene we recently identified as a novel regulator of cellular cholesterol metabolism, encodes a phosphatidylinositol phosphatase that converts PIP2 to phosphatidylinositol-5-phosphate (PI5P). PI5P has also been shown to activate AKT; however, the physiological effects of this pathway are less well understood. In the first in vivo model of Tmem55b modulation, we found that hepatic Tmem55b knockdown in Western diet-fed C57BL/6 mice caused increased body weight, hepatic steatosis, hyperinsulinemia and elevated plasma cholesterol compared to controls. In addition, hepatic expression of insulin-regulated lipogenic genes, including Srebp1c and Dgat2, was increased, suggesting that Tmem55b knockdown promotes lipogenesis. In addition, two genes involved in VLDL secretion, ApoC3 and Mtp, were upregulated. Notably, we observed a significant inverse correlation between TMEM55B expression, quantified in 480 human lymphoblastoid cell lines, with plasma triglyceride, VLDL and APOC3 levels in the cell line donors. These relationships were significantly stronger in individuals with elevated plasma glucose (>110 mg/dL), suggesting that the relationship between TMEM55B and these measures may be enhanced in the insulin resistant state. Based on these findings, we hypothesize that TMEM55B modulates insulin signaling and affects hepatic lipid accumulation, potentially through stimulation of lipogenesis. With the ever-rising incidence of type 2 diabetes, elucidation of a novel pathway by which insulin resistance leads to hepatic steatosis may inform the development of therapeutics used for the prevention or treatment of this disease.
Author Disclosures: M.J. Kim: None. D. Naidoo: None. D. Hu: None. J.J. Woo: None. R.M. Krauss: None. M.W. Medina: None.
- © 2015 by American Heart Association, Inc.