Abstract
Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50 mg/kg or 100 mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-γ (PPAR-γ), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-γ expression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-γ/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most common chronic hepatic disease and is characterized by increased triglyceride accumulation as lipid droplets in hepatocytes
Dyslipidemia, hyperuricemia, and insulin resistance enhance the risk of NAFLD, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis, with prevalence varying from 25% to 40% across different countries [1,2,3]
Two randomized double-blind clinical trials, in which NAFLD treatment was performed for 8 weeks, have shown that curcumin significantly lowered the liver fat content, body mass index, and serum levels of TC, TG, low-density lipoprotein cholesterol (LDL-C), glucose, and uric acid compared with the placebo group [13, 14]
Summary
Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most common chronic hepatic disease and is characterized by increased triglyceride accumulation as lipid droplets in hepatocytes. Two randomized double-blind clinical trials, in which NAFLD treatment was performed for 8 weeks, have shown that curcumin significantly lowered the liver fat content, body mass index, and serum levels of TC, TG, low-density lipoprotein cholesterol (LDL-C), glucose, and uric acid compared with the placebo group [13, 14] These findings suggest that curcumin has the potential to cure dyslipidemia and NAFLD. We found that Curc-mPEG454 could effectively decrease serum TG levels and attenuate hepatic steatosis via activation of cAMP response element-binding (CREB) protein and subsequent negative inhibition of hepatic-specific peroxisome proliferator activated receptor-γ (PPAR-γ) and fatty acid transporter (CD36) expression These findings suggest that Curc-mPEG454 has therapeutic potential in NAFLD by regulating lipid metabolism via the CREB/PPARγ/CD36 pathway. Our results may direct the use of curcumin for the clinical treatment of NAFLD
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