Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors

Woo, Connie W.; Siow, Yaw L.; Pierce, Grant N.; Choy, Patrick C.; Minuk, Gerald Y.; Mymin, David; Karmin, O

doi:10.1152/ajpendo.00518.2004

Cited by 102 publications

(125 citation statements)

References 49 publications

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“…Experimental studies have shown that tHcy may induce hepatic cholesterol biosynthesis (O K et al, 1998;Woo et al, 2005). This may explain why changes in both HDL and LDL cholesterol were positively associated with changes in tHcy in our study.…”

Section: Discussionsupporting

confidence: 50%

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

et al. 2005

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Background: Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population. Objective: To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype. Design: A 1 year follow-up study. Setting: Copenhagen County, Denmark. Subjects: Statistical analyses were based on a population-based sample of 915 men and women aged 30-60 years assessed to be at increased CVD risk at baseline and therefore offered lifestyle intervention and re-examination after one year. Results: None of the studied lifestyle changes -smoking, physical activity, dietary habits, and coffee, tea, and alcohol consumption -was significantly associated with changes in tHcy, either overall, or in any of the MTHFR genotype subgroups. In addition, changes in tHcy did not differ between participants randomized to low-and high-intensity lifestyle intervention. However, the MTHFR TT genotype was associated with a significant decrease in tHcy compared with the CC/CT genotype in which an increase was observed. In addition, changes in tHcy were associated with changes in several of the biological CVD risk markers: weight, total cholesterol, HDL cholesterol, LDL cholesterol and systolic blood pressure. Conclusions: Our results indicate that tHcy may not be reduced by lifestyle changes; additionally, they suggest that tHcy may be related to biological CVD risk markers through a lifestyle independent pathway.

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Section: Discussionsupporting

confidence: 50%

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

et al. 2005

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“…Previous studies have demonstrated that hyperhomocysteinemia could be induced in rats by feeding them a high-methionine diet for 1 month. 22,23 Histological Examination. At the time of killing, the liver was harvested and small pieces were fixed immediately in 10% buffered formalin.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease

Song¹,

Zhou²,

Deaciuc³

et al. 2008

Hepatology

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Although recent evidence suggests that down-regulation of production of the adipocyte hormone adiponectin has pathophysiological consequences for the development of alcoholic liver disease (ALD), the underlying mechanisms are elusive. Abnormal hepatic methionine-homocysteine metabolism induced by prolonged alcohol exposure has been reported both in clinical and experimental studies of ALD. Here, we conducted both in vivo and in vitro experiments to examine the effects of prolonged alcohol exposure on homocysteine levels in adipose tissue, its potential involvement in regulating adiponectin production, and the consequences for ALD. Chronic alcohol exposure decreased the circulating adiponectin concentration and adiponectin messenger RNA (mRNA) and protein levels in epididymal fat pads. Alcohol feeding induced modest hyperhomocysteinemia and increased homocysteine levels in the epididymal fat pad, which was associated with decreased mRNA levels of cystationine ␤-synthase. Betaine supplementation (1.5%, wt/vol) in the alcohol-fed mice reduced homocysteine accumulation in adipose tissue and improved adiponectin levels. Moreover, exogenous homocysteine administration reduced gene expression, protein levels, and secretion of adiponectin in primary adipocytes. Furthermore, rats fed a high-methionine diet (2%, wt/wt) were hyperhomocysteinemic and had decreased adiponectin levels in both plasma and adipose tissue, which was associated with suppressed AMP-activated protein kinase activation in the liver. Mechanistic studies revealed that both inactivation of the extracellular signal regulated kinase 1/2 pathway and induction of endoplasmic reticulum stress response, specifically C/EBP homologous protein expression, may contribute to the inhibitory effect exerted by homocysteine. Conclusion: Chronic alcohol feeding caused abnormal accumulation of homocysteine in adipocytes, which contributes to decreased adiponectin production in ALD. (HEPATOLOGY 2008;47:867-879.)

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“…Results obtained from this group were used as controls. The Hcy concentrations in the plasma and kidney tissue homogenate were measured with the IMx Hcy assay which was based on fluorescence polarization immunoassay technology (Abbott Diagnostics, Abbott Park, IL) (1,37). Plasma creatinine level was determined by using WAKO creatinine kit (Wako Chemical Industries) (39).…”

Section: Methodsmentioning

confidence: 99%

Detrimental role of homocysteine in renal ischemia-reperfusion injury

Prathapasinghe¹,

Siow²,

Karmin³

2007

American Journal of Physiology-Renal Physiology

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Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allografts. Hyperhomocysteinemia, a condition of elevated plasma homocysteine (Hcy) level, is associated with cardiovascular diseases. Recent evidence suggests that Hcy, at higher levels, may be harmful to other organs such as the kidney. In this study, we investigated the role of Hcy in ischemia-reperfusion-induced renal injury. The left kidney of a Sprague-Dawley rat was subjected to either 30-min or 1-h ischemia followed by 1- or 24-h reperfusion. Ischemia-reperfusion caused a significant increase in peroxynitrite formation and lipid peroxidation in kidneys, which reflected oxidative stress. The number of apoptotic cells in those kidneys was also markedly increased. Hcy levels were elevated 2.9- and 1.5-fold in kidneys subjected to ischemia alone or ischemia-reperfusion, respectively. Further investigation revealed that elevation of Hcy level in the kidney upon ischemia-reperfusion was due to reduced activity of cystathionine-β-synthase, a key enzyme in Hcy metabolism. Administration of anti-Hcy antibodies into the kidney not only abolished ischemia-reperfusion-induced oxidative stress and cell death in the kidneys but also restored renal function after 1 h of reperfusion. However, such a protective effect was not sustained after 24 h of reperfusion. In conclusion, ischemia-reperfusion impairs Hcy metabolism in the kidney. Hcy, at elevated levels, is capable of inducing oxidative stress and renal injury. Neutralization of Hcy with antibodies offers transient functional benefit against ischemia-reperfusion-induced oxidative stress and renal injury. These results suggest that Hcy may play a detrimental role in the kidney during ischemia-reperfusion.

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Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors

Cited by 102 publications

References 49 publications

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease

Detrimental role of homocysteine in renal ischemia-reperfusion injury

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