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Background and Aims: Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis. Methods: Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated. Results: DR significantly reduced the number and volume of liver tumors. DR attenu

Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.

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Obesity is becoming a major public health problem worldwide. Making charcoal from wood (“Sumi-yaki”) has been a traditional activity in the southern part of Nagano Prefecture for centuries, with activated charcoal having reported detoxifying effects. However, it is unclear whether activated charcoal also possesses anti-obesity properties. Additionally, since activated charcoal is usually alkaline and might be affected by gastric juice, we evaluated the effect of acidic activated charcoal on high-fat diet (HFD)-induced obesity. This study demonstrated that co-treatment of acidic activated charcoal with a HFD significantly improved obesity and insulin resistance in mice in a dose-dependent manner. Metabolomic analysis of cecal contents revealed that neutral lipids, cholesterol, and bile acids were excreted at markedly higher levels in feces with charcoal treatment. Moreover, the hepatic expressions of genes encoding cholesterol 7 alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase/synthase 1 were up-regulated by activated charcoal, likely reflecting the enhanced excretions from the intestine and the enterohepatic circulation of cholesterol and bile acids. No damage or abnormalities were detected in the gastrointestinal tract, liver, pancreas, and lung. In conclusion, acidic activated charcoal may be able to attenuate HFD-induced weight gain and insulin resistance without serious adverse effects. These findings indicate a novel function of charcoal to prevent obesity, metabolic syndrome, and related diseases.