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 β-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-κB (NF-κB) 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.

Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice

“…Appropriate exercise and adjusted eating habits may improve obesity and NAFLD [4]. In recent years, scholars have pointed out that some pure plant compounds (e.g., resveratrol, curcumin, and maslinic acid) can reduce weight in obese mice and improve NAFLD, mainly by promoting the Sirt1/AMPK signaling pathway [17,25,30]. Our previous study found that phloretin can significantly inhibit the accumulation of oil droplets in differentiated 3T3-L1 adipocytes and significantly inhibit the expression of FAS and adipogenesis-related transcription factors.…”

Plant‐Based Foods and Their Bioactive Compounds on Fatty Liver Disease: Effects, Mechanisms, and Clinical Application

“…The in vitro study showed that curcumin could improve lipid accumulation by increasing the levels of CYP3A and CYP7A while decreasing the level of SREBP-1c in the primary liver cells [ 102 ]. Meanwhile, curcumin could alleviate NAFLD by decreasing the levels of lipid profiles, inhibiting O-GlcNAcylation, as well as reducing the generation of reactive oxygen species (ROS), TNF- α , and interferon- γ (IFN- γ ) in cells [ 103 , 104 ]. An in vivo study reported that oral intake of curcumin attenuated hepatic lipid accumulation in C57BL/6 mice by upregulating the expression of Nrf2 and farnesoid X receptor (FXR) while downregulating the expression of liver X receptor α (LXR α ) [ 102 ].…”

“…An in vivo study reported that oral intake of curcumin attenuated hepatic lipid accumulation in C57BL/6 mice by upregulating the expression of Nrf2 and farnesoid X receptor (FXR) while downregulating the expression of liver X receptor α (LXR α ) [ 102 ]. Also, curcumin alleviated hepatic lipid accumulation and inflammation in C57BL/6J mice by upregulating the SIRT1-AMPK-acetyl-CoA carboxylase (ACC) signaling pathway and inhibiting the O-GlcNAcylation of NF- κ B [ 104 ]. Besides, recent studies also indicated that onion significantly ameliorated hepatic steatosis, ballooning, and lobular and portal inflammation in SD rats and decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TG, insulin, glucose, and the level of TNF- α in hepatocytes [ 105 , 106 ].…”

Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease

“…Furthermore, in humans, CISD2 protein has been found to be upregulated in the skeletal muscle of obese patients after Roux-en-Y gastric bypass surgery [ 36 ]. Additionally, several studies have revealed that certain natural antioxidant treatments, such as curcumin and bitter melon extract, are able to ameliorate NAFLD in mice [ 37 , 38 ]. Interestingly, these two natural products have also been reported to increase Cisd2 levels in mice [ 39 , 40 ].…”