Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways

Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine P-synthase. However, the mechanism by w hich homocysteine promotes the development and progression of hepatic steat osis is unknown. We report here that homocysteine-induced endoplasmic retic ulum (ER) stress activates both the unfolded protein response and the stero l regulatory element-binding proteins (SREBPs) in cultured human hepatocyte s as well as vascular endothelial and aortic smooth muscle cells. Activatio n of the SREBPs is associated with increased expression of genes responsibl e for cholesterol/triglyceride biosynthesis and uptake and with intracellul ar accumulation ofcholesterol. Homocysteine-induced gene expression was inh ibited by overexpression of the ER chaperone, GRP78/BiP, thus demonstrating a direct role of ER stress in the activation of cholesterol/triglyceride b io synthesis. Consistent with these in vitro findings, cholesterol and trig lycerides were significantly elevated in the Livers, but not plasmas, of mi ce having diet-induced hyperhomocysteinemia. This effect was not due to imp aired hepatic export of lipids because secretion of VLDL-triglyceride was i ncreased in hyperhomocysteinemic mice. These findings suggest a mechanism b y which homocysteine-induced ER stress causes dysregulation of the endogeno us sterol response pathway, leading to increased hepatic biosynthesis and u ptake of cholesterol and triglycerides. Furthermore, this mechanism likely explains the development and progression of hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.