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

Abstract

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)...

Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease

“…In order to extend the use of niacin for other indications, we recently showed that niacin prevented the accumulation of fat in liver and regressed pre-existing hepatic steatosis in high-fat fed rat model of NAFLD [16]. In support of our study in experimental NAFLD model, Hu et al in a small uncontrolled study in 39 patients recently showed that niacin therapy (2 g/day) significantly reduced liver fat content in Chinese patients with hypertriglyceridemia [17]. However, hepatocellular mechanisms of action of niacin on pathophysiological events involved in NAFLD are not known.…”

“…Although increased levels of alanine aminotransferase and/or aspartate aminotransferase were observed in some patients taking higher concentrations of niacin as compared to placebo, the levels of these enzymes were not greater than 3 times the upper limit in majority of the patients [57,60]. In fact, in a recent uncontrolled study in dyslipidemic patients with steatosis, niacin administration (2 g/day for 16 weeks) improved liver enzymes including alanine aminotransferase, gammaglutamyl transferase, and alkaline phosphatase [17]. These initial clinical observations are consistent with the potentially beneficial effect of niacin on fat accumulation and antioxidant effects as suggested in this and our original report in a rat NAFLD model [16].…”

Hepatic triacylglycerol synthesis and secretion: DGAT2 as the link between glycaemia and triglyceridaemia

“…It is now evident that by inhibiting DGAT2, niacin would prevent hepatic steatosis associated with endogenous synthesis of fatty acids. Interestingly, the efficacy of niacin as an agent against fatty liver is dependent on DGAT2 polymorphisms of the individuals studied [94], confirming the central role of the enzyme in determining the rate of de novo TAG synthesis and, in turn, of the absolute rates of net de novo TAG synthesis by the liver.…”

Niacin as antidyslipidemic drug

“…In Chinese patients with hypertriglyceridemia extended-release niacin induced a reduction of liver fat content (Hu et al 2012). A polymorphism of DGAT-2 influenced the strength of this effect which demonstrates the significance of DGAT-2 modification within the action of niacin.…”