Abstract
In this study, we aimed to determine the relative effectiveness of common dietary polyphenols or the isoquinoline alkaloid berberine in protecting against molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD) involving changes to cellular lipid metabolism and bioenergetics. In a model of steatosis using HepG2 hepatocytes, exposure of the cells to 1.5 mM oleic acid (OA) for 24 h caused steatosis and distorted cell morphology, induced the expression of mRNA for enzymes that are involved in lipogenesis and fatty acid oxidation (FAS and CPT1A), and impaired indices of aerobic energy metabolism (PPARγ mRNA expression, mitochondrial membrane potential (MMP), and galactose-supported ATP production). Co-treatment with 10 µM of selected polyphenols all strongly protected against the steatosis and changes in cell morphology. All polyphenols, except cyanidin, inhibited the effects on FAS and PPARγ and further increased CPT1A1 expression, suggesting a shift toward increased β-oxidation. Resveratrol, quercetin, catechin, and cyanidin, however not kuromanin or berberine, ameliorated the decreases in MMP and galactose-derived ATP. Berberine was unique in worsening the decrease in galactose-derived ATP. In further investigations of the mechanisms involved, resveratrol, catechin, and berberine increased SIRT1 enzyme activity and p-AMPKαThr172 protein, which are involved in mitochondrial biogenesis. In conclusion, selected polyphenols all protected against steatosis with similar effectiveness, however through different mechanisms that increased aerobic lipid metabolism and mitochondrial function.
Highlights
IntroductionNon-alcoholic fatty liver disease (NAFLD) occurs following the ectopic accumulation of fat in the liver which is the manifestation of an imbalance between lipid influx and removal mechanisms [1]
Non-alcoholic fatty liver disease (NAFLD) occurs following the ectopic accumulation of fat in the liver which is the manifestation of an imbalance between lipid influx and removal mechanisms [1].Initially a benign condition, NAFLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis [2]
Fat droplets in the HepG2 cells treated with polyphenols looked smaller and more dispersed and the cells preserved their eye-shaped morphology compared to the oleic acid (OA) alone condition in which the cells were rounded, swollen, or distorted in morphology
Summary
Non-alcoholic fatty liver disease (NAFLD) occurs following the ectopic accumulation of fat in the liver which is the manifestation of an imbalance between lipid influx and removal mechanisms [1]. NAFLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis [2]. Oleic and palmitic acid are the most abundant fatty acids in the hepatic triglycerides of healthy subjects and patients with NAFLD and contribute to the pathogenesis of the disease [4]. Oleic acid has been shown to be more steatotic than palmitic acid [5] and to induce reactive oxygen species (ROS) generation and TNFα expression [6] which both contribute to the progression of NAFLD to NASH.
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