Abstract
Alcohol consumption is one of the major causes of hepatic steatosis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Ethanol metabolism alters the NAD+/NADH ratio, thereby suppressing the activity of sirtuin family proteins, which may affect lipid metabolism in liver cells. However, it is not clear how long-term ingestion of ethanol eventually causes lipid accumulation in liver. Here, we demonstrate that chronic ethanol ingestion activates peroxisome proliferator-activated receptor γ (PPARγ) and its target gene, monoacylglycerol O-acyltransferase 1 (MGAT1). During ethanol metabolism, a low NAD+/NADH ratio repressed NAD-dependent deacetylase sirtuin 1 (SIRT1) activity, concomitantly resulting in increased acetylated PPARγ with high transcriptional activity. Accordingly, SIRT1 transgenic mice exhibited a low level of acetylated PPARγ and were protected from hepatic steatosis driven by alcohol or PPARγ2 overexpression, suggesting that ethanol metabolism causes lipid accumulation through activation of PPARγ through acetylation. Among the genes induced by PPARγ upon alcohol consumption, MGAT1 has been shown to be involved in triglyceride synthesis. Thus, we tested the effect of MGAT1 knockdown in mice following ethanol consumption, and found a significant reduction in alcohol-induced hepatic lipid accumulation. These results suggest that MGAT1 may afford a promising approach to the treatment of fatty liver disease.
Highlights
Alcoholic liver disease, which is a major cause of morbidity and mortality worldwide, is associated with increased cardiovascular disease and diabetes[1]
monoacylglycerol O-acyltransferase 1 (MGAT1), along with peroxisome proliferator-activated receptor γ (PPARγ), is expressed at low levels in normal liver but is highly up-regulated in diet-induced hepatic steatosis[15]. In this regard, inhibiting MGAT1 expression eventually suppressed hepatic lipid accumulation, as demonstrated by several studies in which MGAT1 is knocked down by adenovirus-mediated small hairpin RNA15, antisense oligonucleotides[17], and liver-specific non-viral small interfering RNA18. These studies are restricted to non-alcoholic hepatic steatosis, we hypothesize that PPARγand its downstream effector MGAT1 may play a role in alcohol-induced hepatic lipid accumulation if sirtuin 1 (SIRT1) affects hepatic PPARγduring ethanol metabolism
Another transcription factor known to play an important role in the pathophysiology of alcoholic hepatic steatosis, sterol regulatory element-binding protein 1c (SREBP1c), was highly expressed along with its target genes, which include liver-type pyruvate kinase (L-PK), stearyl CoA desaturase 1 (SCD1), glycerol phosphate acyltransferase (GPAT), fatty acid elongase 6 (Elvol6), and fatty acid synthase (FAS) (Fig. 1f)
Summary
Alcoholic liver disease, which is a major cause of morbidity and mortality worldwide, is associated with increased cardiovascular disease and diabetes[1]. We reported that increased PPARγ2 expression is a major contributor to high-fat-diet-induced hepatic steatosis, demonstrating that monoacylglycerol O-acyltransferase 1 (MGAT1), a PPARγ-regulated enzyme, plays a critical role in lipid accumulation[15]. MGAT1, along with PPARγ, is expressed at low levels in normal liver but is highly up-regulated in diet-induced hepatic steatosis[15] In this regard, inhibiting MGAT1 expression eventually suppressed hepatic lipid accumulation, as demonstrated by several studies in which MGAT1 is knocked down by adenovirus-mediated small hairpin RNA (shRNA)[15], antisense oligonucleotides[17], and liver-specific non-viral small interfering RNA (siRNA)[18]. These studies are restricted to non-alcoholic hepatic steatosis, we hypothesize that PPARγand its downstream effector MGAT1 may play a role in alcohol-induced hepatic lipid accumulation if SIRT1 affects hepatic PPARγduring ethanol metabolism
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