Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence.

Trimethylamine-N-oxide (TMAO), a derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.

/pdf/berberine-attenuates-choline-induced-atherosclerosis-by-vhpwwtt8mi.pdf

Berberine attenuates choline-induced atherosclerosis by inhibiting trimethylamine and trimethylamine-N-oxide production via manipulating the gut microbiome.

Hepatocellular carcinoma (HCC) is one of the most malignant and poor prognosis tumors, which was increasingly caused by nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) in western countries. In this study, we aimed to investigate the mechanism and therapeutic prospect of berberine in the treatment of NASH-HCC mice. Combination of STZ injection and high fat and high-cholesterol diet (HFHC) was used to establish NASH-HCC model. The effect of berberine intervention is studied from histology, biochemistry and molecular level. Our results showed that administration of berberine to NASH-HCC mice reduced the incidence of tumors and mitigated NASH. Berberine significantly reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total cholesterol (TC). Transcriptome sequencing and bioinformatics analysis identified numberous genes and various pathways may participate in the favorite effect of berberine. Specifically, berberine suppressed the expressions of genes related to lipogenesis, inflammation, fibrosis and angiogenesis. Moreover, our results showed that berberine suppressed phosphorylation of p38MAPK and ERK as well as COX2 expression significantly. This suggested berberine achieved its biological functions mainly by regulating inflammation and angiogenesis genes involving p38MAPK/ERK-COX2 pathways. This study demonstrated the anti-tumor effects of berberine and its possible mechanism, providing a potential drug for treating NASH-HCC.

Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice

The present study investigated the effects of berberine (BBR) on hepatic oxidative stress and the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signalling pathway in rats in which non-alcoholic fatty liver disease (NAFLD) was induced by a high-fat diet. Rats were randomly divided into three groups: The normal control (NC), high-fat diet (HFD) and BBR groups. The NC group received a normal diet, while the other two groups were fed a high-fat diet. The rats in the BBR group were also fed BBR (100 mg/kg body weight) daily. A total of 8 weeks later, serum and liver lipid levels were measured. Hepatic histopathological changes were observed with haematoxylin and eosin and Oil Red O staining. Transmission electron microscopy was performed to observe the ultrastructural changes of the liver. The levels of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) in the liver were measured. Quantitative polymerase chain reaction and western blotting were performed to investigate the expression of genes in the Nrf2/ARE signalling pathway in the liver. Histopathological results demonstrated that rats fed a high-fat diet for 8 weeks developed NAFLD, characterized by hepatic steatosis. BBR significantly decreased the body weight and liver weight. BBR markedly reduced hepatic steatosis, and the serum and liver lipid levels. Hepatic SOD and GSH levels were increased, while MDA levels were decreased by BBR co-administered with a high-fat diet. Additionally, the Nrf2/ARE signalling pathway was revealed to be involved in the protective effect of BBR on rats fed a high-fat diet. In conclusion, BBR may alleviate hepatic oxidative stress in rats with NAFLD, which may be partly attributed to the activation of the Nrf2/ARE signalling pathway.

/pdf/berberine-attenuates-hepatic-oxidative-stress-in-rats-with-49aoi0sbrg.pdf

Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway.

The aim of the present study was to explore the protective effects of Berberine (BBR) against non-alcoholic steatohepatitis (NASH). Male 4-week-old C57BL/6J Apolipoprotein E-deficient (ApoE-/-) mice were divided into the following three groups, which were given different diets: Normal chow diet (SC group); high-fat high-cholesterol diet (HFHC group); and HFHC diet supplemented with BBR (BBR group). Serum biochemical indicators of hepatic function and histological liver tissue changes were evaluated. The expression of neutrophil elastase (NE) and genes involved in the inflammatory response was measured. ApoE-/- mice fed a HFHC diet for 12 weeks developed NASH, characterized by steatosis and liver inflammation. Body weight, and serum triglyceride and cholesterol levels were markedly reduced by BBR. BBR supplementation significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels in mice with HFHC diet-induced NASH, and significantly downregulated hepatic expression and activity of NE, whereas α1-antitrypsin (α1-AT) expression was significantly recovered by BBR (all P<0.05 vs. the HFHC group). Furthermore, treatment with BBR induced a significant reduction in the expression of key genes, including phospoinositide 3-kinase, nuclear factor-κB and interleukin-8, in the C-X-C chemokine receptor type 4 (CXCR4) signaling pathway (all P<0.05 vs. the HFHC group). These results suggest that BBR alleviates NASH in ApoE-/- mice fed a HFHC diet. Restoration of the balance of NE and α1-AT levels, which in turn facilitate the inhibition of the CXCR4 signaling pathways, may be involved in the hepatoprotective effect of BBR. These results indicate that BBR may be a candidate therapeutic agent for the treatment of NASH.

/pdf/berberine-ameliorates-non-alcoholic-steatohepatitis-in-apoe-58dbocgfzq.pdf

Zhen‑Jie Zhuang

Papers

Berberine ameliorates non-alcoholic steatohepatitis in ApoE-/- mice.