Comments for:
Abstract
Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine β-synthase. However, the mechanism by which homocysteine promotes the development and progression of hepatic steatosis is unknown. We report here that homocysteine-induced endoplasmic reticulum (ER) stress activates both the unfolded protein response and the sterol regulatory element–binding proteins (SREBPs) in cultured human hepatocytes as well as vascular endothelial and aortic smooth muscle cells. Activation of the SREBPs is associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake and with intracellular accumulation of cholesterol. Homocysteine-induced gene expression was inhibited by overexpression of the ER chaperone, GRP78/BiP, thus demonstrating a direct role of ER stress in the activation of cholesterol/triglyceride biosynthesis. Consistent with these in vitro findings, cholesterol and triglycerides were significantly elevated in the livers, but not plasmas, of mice having diet-induced hyperhomocysteinemia. This effect was not due to impaired hepatic export of lipids because secretion of VLDL-triglyceride was increased in hyperhomocysteinemic mice. These findings suggest a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides. Furthermore, this mechanism likely explains the development and progression of hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.
Authors
Geoff H. Werstuck, Steven R. Lentz, Sanjana Dayal, Gazi S. Hossain, Sudesh K. Sood, Yuan Y. Shi, Ji Zhou, Nobuyo Maeda, Skaidrite K. Krisans, M. Rene Malinow, Richard C. Austin
Regulation of lipid biosynthesis by inducers of ER stress
Submitter: T. S. Benedict Yen | yen@itsa.ucsf.edu
UCSF and VAMC
Published July 6, 2001
We have read with great interest the article by Werstuck et al. (1), showing that homocysteine not only induces endoplasmic reticulum (ER) stress but also activates the expression of lipid biosynthetic genes. This result parallels our observation that hepatitis B virus large surface protein both activates ER stress and induces the expression of lipid biosynthetic genes (2, 3). Interestingly, however, there is also a significant difference in the two systems. Since the amount of sterol regulatory element-binding protein-1 (SREBP-1) mRNA is also transiently increased by homocysteine treatment and since this increase is blocked by overexpression of BiP (GRP78), homocysteine appears to activate the lipid biosynthetic genes via activation of SREBP-1 by ER stress (1). In contrast, large surface protein does not require sterol regulatory elements to activate the responsive promoters (3). The reason for this difference is not clear. One possibility is the use of different cell lines (HepG2 vs. HuH-7). In any case, it is likely that there may be multiple pathways by which inducers of ER stress can activate lipogenesis and this interesting phenomenon deserves further study.
T. S. Benedict Yen, Department of Pathology, VA Medical Center and University of California, San Francisco, CA.
Ngee Chih Foo, Genetic Immunotherapy Laboratory, Johns Hopkins Singapore Pte Ltd, Singapore.
1. Werstuck, G.H., et al. 2001. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107:1263-1273.
2. Xu, Z., Jensen, G., and Yen, T.S. 1997. Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. J Virol 71:7387-7392.
3. Foo, N.C., and Yen, T.S. 2000. Activation of promoters for cellular lipogenic genes by hepatitis B virus large surface protein. Virology 269:420-425.
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