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Loperamide is a non-prescription medicine normally used for the treatment of diarrhea. The abuse and misuse of loperamide have been demonstrated to have toxic effects on heart. It is still unclear whether the abuse of loperamide can cause hepatic toxicity. The C57BL/6 mice fed with high fat diet (HFD) or normal food diet (NFD) were administrated with loperamide (5 mg/kg/day) intragastrically once a day for two weeks, after that, the feces, blood, hepatic tissues and intestines were harvested for biochemical and histological detection, and the expression of genes related with lipid metabolism was further checked by qRT-PCR (quantitative real-time polymerase chain reaction) and Western blot. The administration of loperamide caused the constipation in mice fed with NFD or HFD. The content of bile acids was significantly reduced in the feces of mice treated with loperamide, but the content of bile acids was significantly increased in the liver of these mice. The results of HE staining showed that loperamide administration caused the damage of hepatic tissues, especially for mice fed with HFD. The expression of genes related with the biosynthesis of cholesterol and bile acids, including Hmgcr, Lss, Sqle, Fdps, Idi1, Mvk, Cyp7a1 and Ch25h, was all upregulated in the liver of mice treated with loperamide. Conversely, the expression of Abcg5, Abcb11 and Abcc2, which encode genes for transporting cholesterols and bile acids from hepatocytes to bile respectively, was downregulated in the liver of mice treated with loperamide. At the same time, the expression of Fabp6 and Slc51a, which transport bile acids from intestinal lumen into the blood, was all upregulated in the ileum of mice treated with loperamide. The expression of SHP, which inhibits the transcription of Cyp7a1 in hepatocytes, was significantly downregulated in the hepatic tissues of mice treated with loperamide. These results demonstrated that administration of loperamide caused excessive accumulation of bile acids in the liver of mice via upregulating genes for biosynthesis of cholesterol and bile acid and downregulating genes for discharging cholesterol and bile acids in hepatocytes of mice, moreover, the downregulation of SHP in hepatic tissues might be one of the mechanisms of it, especially for mice fed with HFD.

Exposure of humans to second-hand smoking (SHS) increases glucose and lipid metabolic disorders. The link of hepatic metabolic dysfunction to environmental cigarette smoking has been noticed, but the related mechanism is still unclear. C57BL/6 mice with normal food diet (NFD) or high fat diet (HFD) were exposed to 15 min cigarette smoking twice a day in a 0.038 m3 box for 4 weeks, and the concentration of nicotine in the air of the box was 21.05 mg/m3 during the smoke exposure. Liver tissues and serum were collected for gene expression and biochemistry test. The fecal microbiota was also checked through 16S rDNA sequences. Cigarette smoking exposure increased the accumulation of total cholesterol (TC) in liver, and the expression of cholesterol synthesis-related genes was upregulated. The expression of CYP8B1 protein was significantly down-regulated, and the ratio of cholic acid (CA) to chenodeoxycholic acid (CDCA) was significantly reduced in the liver of mice exposed to cigarette smoking especially for HFD group. Cigarette smoking exposure caused insulin resistance in the liver of mice with HFD. The composition of the gut microbiota was altered with the exposure of cigarette smoking, and the change of the distribution of primary bile acids might be one of the reasons. It was concluded that cigarette smoking would break the homeostasis of cholesterol and bile acids metabolism and changed the composition of gut microbiota. Our discoveries confirmed that smoking bans are important for the public health.