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Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation.

ABSTRACT: The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo O-GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of O-linked ?-N-acetylglucosamine (O-GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of O-GlcNAcylation on nuclear factor-?B (NF-?B) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits O-GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper-O-GlcNAcylation, including cancer.

SUBMITTER: Lee DE

PROVIDER: S-EPMC6893521 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of <i>O</i>-GlcNAcylation.

Lee Da Eun DE Lee Su Jin SJ Kim Su Ji SJ Lee Hyun-Shik HS Kwon Oh-Shin OS

Nutrients 20191108 11

The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis ...[more]

PMID: 31717261

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Project description:Background & aimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.

Dataset Information

Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation.

Publications

Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of <i>O</i>-GlcNAcylation.

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