Biological targets of berberine hydrochloride and the mechanisms by which it alleviates metabolic-associated fatty liver disease

Abstract

<p indent="0mm">Metabolic-associated fatty liver disease (MAFLD) is a common disease worldwide and is closely related to cardiovascular disease, obesity, diabetes and other metabolic diseases. However, there is no efficient medication available yet. Researches on potential drugs, including antioxidants, insulin sensitizers and lipid-lowering drugs, have indicated that these drugs are effective in reducing the liver fat content and some histological lesions but have limited effects in alleviating liver fibrosis. Berberine hydrochloride (BBR) is an isoquinoline alkaloid derived from many medicinal plants. It was used as an anti-diarrhoea drug in the early stage. However, a large number of studies have shown that it has rich pharmacological effects in the protection against cardiovascular diseases, cancers and other aspects. Increasing evidence has indicated that BBR can regulate metabolism and has beneficial effects on MAFLD. In the target organ of the liver, BBR can activate AMPK by regulating the phosphorylation of AMPK. This phosphorylation inhibits the expression of downstream genes related to lipid synthesis and metabolism, and thus improves hepatic steatosis. The mitochondrial membrane protein UCP2 is considered to be one of the key proteins in reducing fatty liver that acts by targeting liver mitochondria to improve cellular oxidative stress. Improving insulin resistance may also be one of the important mechanisms by which BBR alleviates MAFLD. This mechanism is mainly related to the glucose transporter and insulin resistance-related protein IRS. However, BBR is absorbed and first eliminated in the small intestine. More than 99% of BBR does not enter the bloodstream. It is speculated that BBR mainly plays a biological role in alleviating hepatic steatosis by acting through the intestinal tract, but the specific mechanism and target of BBR remain unclear. Some studies have indicated that the effect of BBR on the improvement of the intestinal microenvironment and the inhibition of intestinal lipid uptake may be the key mechanism. BBR can alleviate MAFLD by improving intestinal dysregulation, reducing blood lipids and inflammatory cytokines, and restoring bile acids. In addition, BBR, absorbed by intestinal epithelial cells, can regulate intestinal lipid uptake. Soat2 may be an important regulatory target of BBR in the intestine. By regulating Soat2, BBR can inhibit the expression of proteins related to lipid uptake in the intestinal epithelium and inhibit the uptake of free fatty acids and cholesterol in the intestinal tract. Recent studies have found that Soat2 is a target gene of hepatic X receptor (LXRα) transcriptional regulation. If the LXR inverse activator acts only in the gut, it can effectively inhibit Soat2 expression, reduce cholesterol reabsorption, and lower plasma LDL levels. Therefore, the LXR-SOAT2 regulatory mechanism may also be involved in the regulation of fatty acid uptake in the gut by BBR. In this review, we briefly summarize the mechanism by which BBR acts in the direct regulation of liver lipid metabolism, including activating the AMPK pathway and alleviating liver inflammation and oxidative stress. A potential biological target of BBR in the intestinal tract that could ameliorate MAFLD by improving the intestinal microenvironment and inhibiting intestinal lipid uptake was also reviewed.