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

Wang, Zhigang; Tong, Yao; Song, Zhenyuan

doi:10.1194/jlr.m007948

Cited by 53 publications

(36 citation statements)

References 36 publications

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“…A recent study in pigs, in which the DGAT2 gene is 90% identical to the homologous gene of humans, showed that an A/G variation in the 3 ′ UTR of DGAT2 was resulted in marked reduction in hepatic TG as well as plasma TG, diacylglycerol, and FFA levels ( 11 ). In vitro and animal studies also suggested that upregulation of DGAT2 may be involved in the hepatic fat accumulation induced by chronic alcohol consumption ( 20 ). Niacin was demonstrated to directly and noncompetitively inhibit the activity of DGAT2 in cell lines ( 9 ), and our study is the fi rst to show a signifi cant association between the DGAT2 polymorphism and the liver fat changes in response to niacin treatment in patients with dyslipidemia.…”

Section: Discussionmentioning

confidence: 66%

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Chu

Yamashita

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Nonalcoholic fatty liver disease (NAFLD) characterized by excessive accumulation of intrahepatic triglycerides is associated with multiple metabolic abnormalities that are important cardiovascular risk factors, including increased plasma triglycerides (TG), obesity, insulin resistance, diabetes, and the metabolic syndrome ( 1, 2 ). Hepatic steatosis, the earliest stage of the disease, arises from an imbalance between hepatic TG acquisition and removal ( 3 ). Increased supply to the liver of free fatty acids (FFA), the substrates for hepatic TG synthesis, from diet and adipose tissue and through increased de novo lipogenesis, promotes hepatic steatosis ( 3, 4 ).Nicotinic acid or niacin, one of the naturally occurring B vitamins (vitamin B3), effectively reduces plasma TG levels. This effect was initially thought to be attributable to its antilipolytic effect in adipose tissue, thereby reducing FFA release from adipocytes and decreasing FFA fl ux to the liver ( 5, 6 ). However, although niacin initially reduces plasma FFA concentrations, this reduction is actually followed by a rebound within 1 to 9 h postdose, depending on the formulation used, and long-term treatment with niacin is associated with increases in plasma FFA, glucose, and insulin resistance ( 7,8 ). These observations suggest that the reduction of the FFA delivery to the liver may not be the main mechanism explaining the consistent and maintained plasma TG-lowering effect of niacin.Recent in vitro and animal studies suggested that the TG-lowering effect of niacin might be mediated by its direct and noncompetitive inhibitory effect on hepatic diacylglycerol acyltransferase-2 (DGAT2), a key enzyme that catalyzes the fi nal step of TG synthesis ( 9, 10 ). Inhibition of mouse Dgat2 with antisense oligonucleotides in mice with obesity induced by high-fat diet or leptin-defi ciency Abstract Niacin reduces plasma triglycerides, but it may increase free fatty acids and insulin resistance during longterm treatment. We examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 ( DGAT2 ) polymorphisms infl uenced this effect. The 39 patients (baseline liver fat content: 12.8 ± 7.6%, triglycerides: 3.30 ± 1.67 mmol/l) were treated with niacin, gradually increasing the dose to 2 g/day for a total of 23 weeks. The liver fat content and visceral/subcutaneous fat was measured before and after treatment. Subjects were genotyped for the DGAT2 rs3060 and rs101899116 polymorphisms. There were signifi cant ( P < 0.001) reductions in plasma triglycerides ( ؊ 34.9 ± 37.6%), liver fat content ( ؊ 47.2 ± 32.8%), and visceral fat ( ؊ 6.3 ± 15.8%, P < 0.05) after niacin treatment. Mean body weight decreased by 1.46 ± 2.7% (1.17 ± 2.44 kg, P < 0.001) during the study, but liver fat changes remained signifi cant after adjustment for age, gender, and body weight changes [mean absolute change (95% CI): ؊ 6.1% ( ؊ 8.0, ؊ 4.3)...

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Section: Discussionmentioning

confidence: 66%

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Chu

Yamashita

et al. 2012

Journal of Lipid Research

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“…However, administration of TAM decreased DGAT2 expression in CTL mice and both mouse models. DGAT2 is the rate-limiting enzyme catalyzing the final step in triglyceride synthesis and exerts an important role in the development of fatty liver diseases (Choi et al, 2007;Yu et al, 2005;Wang et al, 2010). Thus, these results suggested that TAM did not increase but instead decreased the fat accumulation after the onset of steatosis and NASH.…”

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confidence: 58%

“…In contrast, MAPK family members such as ERK exert protective and anti-apoptotic effects upon activation by an upstream kinase and regulate a number of major cellular functions, such as cell proliferation, differentiation and inflammation (Czaja et al, 2003). Furthermore, ERK activation is reported to decrease DGAT2 expression (Wang et al, 2010;Tsai et al, 2007). Increased JNK phosphorylation has been reported in steatosis and NASH model mice (Hirosumi et al, 2002).…”

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confidence: 99%

“…Fat makes the liver vulnerable to endotoxins and ischemic reperfusion damage, impairs liver regeneration (Uesugi et al, 2001) and causes hepatic insulin resistance (Kim et al, 2001). Acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) is the final step and rate limiting reaction in triglyceride synthesis (Choi et al, 2007;Yu et al, 2005;Wang et al, 2010). Reactive oxygen species (ROS) together with tumor necrosis factor (TNF) α and monocyte chemoattractant protein (MCP) -1 represent the "second hit" (Jou et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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-Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

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“…Small end-products of lipid peroxidation, such as 4-HNE and other aldehydes transported by activated granulocytes/monocytes, may facilitate and maintain generalized inflammation (25). The plasma adiponectin level is determined by complex intracellular regulatory mechanisms involved in gene expression, post-transcriptional/translational modification, and trafficking/secretion processes (26,27). Adiponectin is predominantly produced and secreted into circulation by adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Association of 4-hydroxynonenal with classical adipokines and insulin resistance in a Chinese non-diabetic obese population

Guo¹,

Zhang²,

Zhang³

et al. 2017

Nutr Hosp

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Background: The prevalence of obesity is increasing worldwide. Oxidative stress plays an etiological role in a variety of obesity-related metabolic disorders. 4-hydroxynonenal (4-HNE) is the most abundant and reactive aldehydic product derived from the peroxidation of n-6 polyunsaturated fatty acids with diverse biological effects that are not well detailed. Obesity is associated with decreased plasma adiponectin concentrations and increased production of lipid peroxidation products, including 4-HNE, in adipose tissue. There may be some association between the level of adipokines and 4-HNE. Material and methods:To analyze the associations between 4-HNE and classical adipokines, namely, adiponectin and leptin in a Chinese population, the plasma 4-HNE, adiponectin and leptin levels of 160 non-diabetic obese (NDO) patients and 160 healthy subjects were determined by ELISA, and their associations with adiposity, glucose, lipid profi les, insulin secretion and insulin sensitivity were studied. Results: Plasma 4-HNE levels were signifi cantly increased in patients with NDO compared with healthy controls (p < 0.01). 4-HNE was negatively correlated with adiponectin and positively correlated with leptin. The plasma levels of 4-HNE were signifi cantly correlated to several parameters involved in body mass index (BMI) and insulin resistance (IR). The 4-HNE levels were positively correlated with BMI and negatively correlated with insulin sensitivity. Conclusion: We conclude that 4-HNE is associated with the secretion of adiponectin and leptin and is correlated with IR in NDO humans. These fi ndings indicate a pro-infl ammatory role of 4-HNE in NDO patients, which supports the potential role of 4-HNE in the development of obesity-related disorders.

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

Cited by 53 publications

References 36 publications

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Association of 4-hydroxynonenal with classical adipokines and insulin resistance in a Chinese non-diabetic obese population

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