Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway

Kharbanda, Kusum K.; Mailliard, Mark E.; Baldwin, Cheryl R.; Beckenhauer, Harriet C.; Sorrell, Michael F.; Tuma, Dean J.

doi:10.1016/j.jhep.2006.08.024

Cited by 175 publications

(230 citation statements)

References 26 publications

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“…Decreased phosphatidylethanolamine methyltransferase activity due to disrupted transmethylation reactions and subsequently decreased phosphatidylcholine synthesis contributes to alcohol-induced fatty liver via suppressing VLDL formation and secretion. In agreement with this observation, improvement of methionine metabolism by betaine supplementation alleviates phosphatidylethanolamine methyltransferase suppression and attenuates alcoholic fatty liver ( 37 ). In line with previous studies, our results show that chronic alcohol exposure is associated with suppressed hepatic transmethylation reactions, evidenced by decreased SAM and increased SAH levels in the liver, leading to a signifi cantly decreased SAM:SAH ratio.…”

Section: Inhibition Of Methyltransferase Suppressed Mek/ Erk1/2 Activsupporting

confidence: 92%

Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

Wang

Tong

Song

2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org Alcoholic liver disease (ALD) continues to be an important health problem in the United States. Although much progress has been made over the past two decades, the mechanisms involved in its initiation and progression remain to be fully understood. The disease is characterized by early steatosis, subsequent steatohepatitis (steatosis with infl ammatory cell infi ltration and necrosis), and, in some instances, progression to fi brosis and/or cirrhosis ( 1, 2 ). Excessive neutral fat accumulation in hepatocytes (steatosis) is the most common and earliest response of the liver to chronic alcohol consumption ( 3 ) and plays a critical role in disease progression. Hepatic steatosis results from an imbalance between intrahepatic triglyceride (TG) production and removal. Both uptake of free fatty acids (FAs) to the liver and de novo synthesis contribute to hepatic TG production, whereas FA ␤ -oxidation and formation of very low density lipoprotein (VLDL) particles contribute to hepatic TG removal.The fi nal step and rate-limiting reaction in TG synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT), which covalently joins a fatty acyl-CoA and a diacylglycerol (DG) molecule to form TG. In mammals, DGAT occurs in two isoforms, DGAT1 and DGAT2, from distinct gene families ( 4, 5 ). Although both isoforms are widely expressed and present at high levels in white adipose tissue, DGAT1 is most highly expressed in the small intestine, whereas DGAT2 is primarily expressed in the liver ( 4, 6 ). Evidence suggest that the two enzymes play different roles in TG metabolism, with DGAT2 participating in steatosis and DGAT1 in VLDL synthesis. Overexpression of liver-specifi c DGAT2 in mice results in hepatic Abstract The mechanisms involved in the development of alcoholic liver disease (ALD) are not well established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a signifi cant suppression of hepatic MAPK/ERK kinase/extracellular regulated kinase 1/2 (MEK/ERK1/2) activation. In vitro studies demonstrated that specifi c inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, whereas epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-L -cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the benefi cial effects of betaine supplementation in ALD w...

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Section: Inhibition Of Methyltransferase Suppressed Mek/ Erk1/2 Activsupporting

confidence: 92%

Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

Wang

Tong

Song

2010

Journal of Lipid Research

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“…ERK-, MEK-, and mitogenactivated protein kinase-related pathways are regulated and regulate Jun N-terminal kinase (JNK) expression, which has a pivotal role in obesity and insulin resistance [52]. Phosphatidylcholine, another component of the RA preparation, protects against oxidative stressmediated liver damage [53,54]. It is unlikely that the treatment effects are related to the vitamin E component, which is much lower (60 IU/ day) than doses with documented efficacy [4].…”

Section: Discussionmentioning

confidence: 99%

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

Loguercio

Andreone

Brisc

et al. 2012

Free Radical Biology and Medicine

219

147

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The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with Free

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“…12 A recent study by Kharbanda et al 37 demonstrated that betaine attenuated alcoholic steatosis by attenuating the chronic alcohol consumption-induced decrease in SAM/SAH ratio in the liver and its subsequent inhibition of methyltransferases involved in the phosphatidylcholine synthesis. Based on our finding that homocysteine suppressed adiponectin production, we hypothesize that restoration of adiponectin levels through the prevention of hyperhomocysteinemia may also contribute to the beneficial impact of betaine in ALD.…”

Section: Discussionmentioning

confidence: 99%

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

Song¹,

Zhou²,

Deaciuc³

et al. 2008

Hepatology

114

125

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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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Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway

Cited by 175 publications

References 26 publications

Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

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

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