ArticleThe Journal of clinical investigation2001
Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.
Article in The Journal of clinical investigation, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 252 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
252 citing papers in PubMed, 700 citations in OpenAlex.
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- PPARγ-dependent and -independent regulation of methionine metabolism by diet-induced obesity and fasting in male mice.bioRxiv : the preprint server for biology · 2026Article
- Homocysteine levels and cancer risk in hypertensive adults across MTHFR C677T genotypes.Scientific reports · 2026Article
- PPARγ-dependent and -independent regulation of genes involved in hepatic methionine cycle in fasted or diet-induced obese mice.PloS one · 2026Article
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- Association Between Plasma Homocysteine, Folate, Vitamin B12 Levels, and Metabolic Dysfunction Indices in Elderly with Arterial Stiffness.Journal of clinical medicine · 2025Article
- MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives.Molecular oncology · 2025Review
- Roles of X-box binding protein 1 in liver pathogenesis.Clinical and molecular hepatology · 2025Review
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- Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency.Scientific reports · 2024Article
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- TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells.International journal of molecular sciences · 2024Article
- Alternate day fasting aggravates atherosclerosis through the suppression of hepatic ATF3 inLife metabolism · 2024Article
- Association of plasma homocysteine with peripheral arterial disease in the hypertensive adults: A cross-sectional study.Journal of clinical hypertension (Greenwich, Conn.) · 2024Article
192 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine beta-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.