Citations to this article


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.


Geoff H. Werstuck ... M. Rene Malinow, Richard C. Austin


Total citations by year in Crossref

Year: 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 Total
Citations: 9 19 6 12 14 17 18 15 20 9 16 9 8 4 176
Citation information

Citations to this article in Crossref (176)

Title and authors Publication Year
Deficiency of cystathionine gamma-lyase and hepatic cholesterol accumulation during mouse fatty liver development
S Mani, H Li, G Yang, L Wu, R Wang
Science Bulletin 2015
The relevance of epigenetics to occlusive cerebral and peripheral arterial disease
SM Krishna, AF Trollope, J Golledge
Clinical Science 2015
Melatonin ameliorates ER stress-mediated hepatic steatosis through miR-23a in the liver
SJ Kim, HS Kang, JH Lee, JH Park, CH Jung, JH Bae, BC Oh, DK Song, WK Baek, SS Im
Biochemical and Biophysical Research Communications 2015
Acid sphingomyelinase-ceramide system in steatohepatitis: A novel target regulating multiple pathways
C Garcia-Ruiz, JM Mato, D Vance, N Kaplowitz, JC Fernández-Checa
Journal of Hepatology 2015
Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions
S Nakano, I Ishii, K Shinmura, K Tamaki, T Hishiki, N Akahoshi, T Ida, T Nakanishi, S Kamata, Y Kumagai, T Akaike, K Fukuda, M Sano, M Suematsu
Journal of Molecular Medicine 2015
Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells
D Gurda, L Handschuh, W Kotkowiak, H Jakubowski
Amino Acids 2015
Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?
R Creegan, W Hunt, A McManus, SR Rainey-Smith
British Journal of Nutrition 2015
Involvement of multiple pathways in the protection of liver against high-fat diet-induced steatosis by betaine
CW Ahn, YJ Choi, SH Hong, DS Jun, JD Na, YJ Choi, YC Kim
Journal of Functional Foods 2015
SRT1720 counteracts glucosamine-induced endoplasmic reticulum stress and endothelial dysfunction
TV Fiorentino, T Procopio, E Mancuso, GP Arcidiacono, F Andreozzi, F Arturi, A Sciacqua, F Perticone, ML Hribal, G Sesti
Cardiovascular Research 2015
Resolvin D1 reduces ER stress-induced apoptosis and triglyceride accumulation through JNK pathway in HepG2 cells
TW Jung, HJ Hwang, HC Hong, HY Choi, HJ Yoo, SH Baik, KM Choi
Molecular and Cellular Endocrinology 2014
Yessotoxin induces ER-stress followed by autophagic cell death in glioma cells mediated by mTOR and BNIP3
JA Rubiolo, H López-Alonso, P Martínez, A Millán, E Cagide, MR Vieytes, FV Vega, LM Botana
Cellular Signalling 2014
How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver?:
S Wang, RJ Kaufman
Current Opinion in Lipidology 2014
Effect of methionine-deficient and methionine-supplemented diets on the hepatic one-carbon and lipid metabolism in mice
AF Aissa, V Tryndyak, A Conti, S Melnyk, TD Gomes, ML Bianchi, SJ James, FA Beland, LM Antunes, IP Pogribny
Molecular Nutrition & Food Research 2014
Oral glucosamine sulfate supplementation does not induce endoplasmic reticulum stress or activate the unfolded protein response in circulating leukocytes of human subjects
CS McAlpine, DR Beriault, T Behdinan, Y Shi, GH Werstuck
Canadian Journal of Physiology and Pharmacology 2014
Apolipoprotein A-I and adenosine triphosphate-binding cassette transporter A1 expression alleviates lipid accumulation in hepatocytes: ApoA-I/ABCA1 expression reduces lipids
W Liu, L Qin, H Yu, F Lv, Y Wang
Journal of Gastroenterology and Hepatology 2014
Cholesterol biosynthesis and ER stress in peroxisome deficiency
PL Faust, WJ Kovacs
Biochimie 2014
Paeoniflorin protects cells from GalN/TNF- -induced apoptosis via ER stress and mitochondria-dependent pathways in human L02 hepatocytes
Z Jiang, W Chen, X Yan, L Bi, S Guo, Z Zhan
Acta Biochimica et Biophysica Sinica 2014
Disturbance of endogenous hydrogen sulfide generation and endoplasmic reticulum stress in hippocampus are involved in homocysteine-induced defect in learning and memory of rats
MH Li, JP Tang, P Zhang, X Li, CY Wang, HJ Wei, XF Yang, W Zou, XQ Tang
Behavioural Brain Research 2014
Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial
Z Asemi, M Karamali, A Esmaillzadeh
Molecular Nutrition & Food Research 2014
The E3 Ubiquitin Ligase gp78 Protects Against ER Stress in Zebrafish Liver
Z Chen, P Ballar, Y Fu, J Luo, S Du, S Fang
Journal of Genetics and Genomics 2014
Oxidative Stress and Disease
D Uzi, D Alkam, B Tirosh
Oxidative Stress and Disease 2014
Contribution of calumin to embryogenesis through participation in the endoplasmic reticulum-associated degradation activity
S Yamamoto, T Yamazaki, S Komazaki, T Yamashita, M Osaki, M Matsubayashi, H Kidoya, N Takakura, D Yamazaki, S Kakizawa
Developmental Biology 2014
Sulforaphane Attenuates Homocysteine-Induced Endoplasmic Reticulum Stress through Nrf-2-Driven Enzymes in Immortalized Human Hepatocytes
C He, B Li, W Song, Z Ding, S Wang, Y Shan
Journal of Agricultural and Food Chemistry 2014
Glycogen Synthase Kinase 3α Deficiency Attenuates Atherosclerosis and Hepatic Steatosis in High Fat Diet–Fed Low Density Lipoprotein Receptor–Deficient Mice
NS Banko, CS McAlpine, DE Venegas-Pino, P Raja, Y Shi, MI Khan, GH Werstuck
The American Journal of Pathology 2014
Polymorphisms in methylenetetrahydrofolate reductase gene: Their impact on liver steatosis and fibrosis of chronic hepatitis c patients
E Altintas, ZM Altintas, O Sezgin, E Ucbilek, E Nayir, ME Erdal, A Polat, G Orekeci
Open Journal of Gastroenterology 2014