Glycyrrhetinic acid regulates impaired macrophage autophagic flux in the treatment of non-alcoholic fatty liver disease

Abstract

Macrophages are involved in hepatocyte steatosis and necroinflammation and play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Impaired autophagy function (decreased autophagy or blocked autophagic flow) leads to cell damage and death and promotes NAFLD progression. The experimental and clinical research of glycyrrhetinic acid (GA) in the treatment of NAFLD has gradually attracted attention with clear pharmacological activities such as immune regulation, antiviral, antitumor, antioxidant, liver protection, and anti-inflammatory. However, the effects of GA on the STAT3-HIF-1α pathway and autophagy in macrophages are still unclear, and its mechanism of action in the treatment of NAFLD remains to be further elucidated. We constructed a NAFLD mouse model through a high-fat and high-sugar diet to investigate the therapeutic effects of GA. The results showed that GA reduced weight, improved the pathological changes and hepatic lipid deposition of liver, and abnormally elevated the levels of serum biochemical (AST, ALT, TG, T-CHO, LDL-C, and HDL-C) and inflammatory indexes (IL-1β, IL-4, IL-6, MCP-1, and TNF-α) in NAFLD mice. Further examination revealed that GA ameliorates excessive hepatic macrophage infiltration and hepatocyte apoptosis. The results of the cell experiments further elaborated that GA modulated the PA-induced macrophage STAT3-HIF-1α pathway and ameliorated impaired autophagic flux (blockade of autophagosome–lysosome fusion) and overactivation of inflammation. Excessive hepatocyte apoptosis caused by the uncontrolled release of inflammatory cytokines was also suppressed by GA.ConclusionThis study demonstrated that GA could regulate the STAT3-HIF-1α pathway of macrophages, ameliorate the impaired autophagy flux, and reduce the excessive production of inflammatory cytokines to improve the excessive apoptosis of liver cells, thus playing a therapeutic role on NAFLD.

Programmed cell death and lipid metabolism of macrophages in NAFLD

“…Licochalcone B (LicoB), a main component of the traditional medicinal herb licorice, is a specific inhibitor of the NLRP3 inflammasome which directly binds to never in mitosis A-related kinase 7 (NEK7) and inhibits the interaction between NLRP3 and NEK7 ( 199 ). Glycyrrhetinic acid, another active ingredient of licorice, can also improve the damaged autophagy flux and reduce the excessive production of inflammatory cytokines such as TNF-α, IL-6 and IL-1β by regulating the STAT3-HIF-1 pathway of macrophages ( 200 ). Curcumin and berberine, two of the most studied natural products for the treatment of NAFLD, have shown positive results in several clinical trials ( 201 , 202 ).…”

Bazi Bushen maintains intestinal homeostasis through inhibiting TLR4/NFκB signaling pathway and regulating gut microbiota in SAMP6 mice

“…According to the manufacturer's instructions, IL‐6, IL‐1β, and TNF‐α in colon tissues were measured using commercial ELISA kits 29 . The microplate reader (ThermoFisher, Waltham, MA, USA) was used to determine the optical density (OD) value at 450 nm.…”

“…Western blot analysis of the colon samples was conducted as previously described. 29 The colon samples were put into an ice-cold radio immunoprecipitation assay (RIPA) buffer solution for homogenate preparation. After centrifugation, we used a BCA kit to measure the protein concentration of the lysates.…”

Current Advances in the Regulatory Effects of Bioactive Compounds from Dietary Resources on Nonalcoholic Fatty Liver Disease: Role of Autophagy

“…Additionally, mitochondrial STAT3 suppresses autophagy induced by oxidative stress, potentially hindering mitophagy conducive to promoting survival. Treatment with glycyrrhetinic acid reversed alterations of macrophage STAT3–hypoxia inducible factor-1α (HIF-1α) signaling pathways and deficient autophagy flux caused by a high-fat and high-sugar diet, thereby improving NF-κB-mediated inflammation and displaying therapeutic effects for NAFLD management. , …”

“…Treatment with glycyrrhetinic acid reversed alterations of macrophage STAT3− hypoxia inducible factor-1α (HIF-1α) signaling pathways and deficient autophagy flux caused by a high-fat and high-sugar diet, thereby improving NF-κB-mediated inflammation and displaying therapeutic effects for NAFLD management. 105,106…”