The Potential Mechanisms of Berberine in the Treatment of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a globally observed metabolic disease with high prevalence both in adults and children. However, there is no efficient medication available yet. Increased evidence indicates that berberine (BBR), a natural plant product, has beneficial effects on NAFLD, though the mechanisms are not completely known. In this review, we briefly summarize the pathogenesis of NAFLD and factors that influence the progression of NAFLD, and focus on the potential mechanisms of BBR in the treatment of NAFLD. Increase of insulin sensitivity, regulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, improvement of mitochondrial function, alleviation of oxidative stress, LDLR mRNA stabilization, and regulation of gut microenvironment are the major targets of BBR in the treatment of NAFLD. Additionally, reduction of proprotein convertase subtilisin/kexin 9 (PCSK9) expression and DNA methylation are also involved in pharmacological mechanisms of berberine in the treatment of NAFLD. The immunologic mechanism of BBR in the treatment of NAFLD, development of berberine derivative, drug combinations, delivery routes, and drug dose can be considered in the future research.

Keywords: adenosine monophosphate-activated protein kinase; berberine; insulin resistance; mechanism; nonalcoholic fatty liver disease.

Figure 1

The disease spectrum of NAFLD and the factors that influence the progression of NAFLD. (A) The spectrum of NAFLD ranges from simple steatosis to NASH and cirrhosis. Simple steatosis is characterized by the ectopic accumulation of lipid droplets in the cytoplasm of hepatocytes without hepatocyte injury, inflammation, and fibrosis histologically. Steatosis is self-limited and can be reversed by lifestyle modifications. Steatosis can develop to NASH, which differs from simple steatosis in the presence of hepatocyte injury, inflammation, and fibrosis. Long-term NASH leads to cirrhosis. In NASH-related cirrhosis, normal liver structure is damaged and replaced by type 1 collagen, and pseudolobules are formed; (B) The factors that influence the progression of NAFLD include energy excess, obesity, insulin resistance, genetic factors, gender and ethnic difference, gut microbiota, hypoxia, oxidative stress and lipid peroxidation, inflammatory cytokines, liver iron overload, endogenous cannabinoids receptor 1, and epigenetic modifications. Energy excess includes diet and sedentary lifestyle.

Figure 2

The potential mechanisms of berberine in the treatment of NAFLD. (A–E) BBR improves insulin resistance via directly triggering insulin secretion, increasing IRSs expression, increasing InsR expression through PKC activation, inducing GLUT4 translocation to cell membrane and decreasing ER stress; (F) BBR activates AMPK in both direct way and indirect way. The activation of AMPK decreases lipogenesis, increases energy consumption, promotes FA oxidation, and triggers adiponectin multimerization to HMW multimer; (G) BBR inhibits mitochondrial respiratory complex I and enhances AMP/ATP ratio, resulting in the activation of AMPK. In addition, BBR increases the expression of sirtuin 3, improving mitochondrial function and alleviating oxidative stress. It is controversial whether BBR induces UCP2 expression; (H) BBR stabilizes LDLR mRNA and increases LDLR expression, which depends on ERK activation; (I) BBR regulates intestinal microbiota, reduces the entry of microbial productions, and repairs gut permeability caused by damaged tight junctions; (J) Other mechanisms containing reduction of PCSK9 expression and DNA methylation may be involved.