Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease.

Hu Li,Jing Jiang,Lei Lei,Jian-Rui Li,Zong-Gen Peng,Xue-Kai Wang,Biao Dong,Han Sun,Jia-Li Tan,Hong-Ying Li,Mei-Xi Wang,Nan-Nan Liu,Jian-Dong Jiang

doi:10.3389/fphar.2022.843872

Abstract

Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and β-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD), a common liver disease affecting a quarter of the world’s population, includes nonalcoholic fatty liver (NAFL) characterized by mere excessive lipid accumulation in the liver and nonalcoholic steatohepatitis (NASH), characterized by inflammation and/or fibrosis and even cirrhosis (Eslam et al, 2020; Huang et al, 2021)
We demonstrated that the combination of bicyclol and berberine exerted better preventive and therapeutic effects than monotherapy for NAFLD in mice induced by Western diet (WD) or WD/CCl4
C57BL/6J mice were treated with WD or WD mingled with low/high dose of bicyclol and/or berberine by free feeding for 16 weeks, and the low-fat, low-cholesterol (LFLC) diet was set as normal diet control (Figure 1A)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), a common liver disease affecting a quarter of the world’s population, includes nonalcoholic fatty liver (NAFL) characterized by mere excessive lipid accumulation in the liver and nonalcoholic steatohepatitis (NASH), characterized by inflammation and/or fibrosis and even cirrhosis (Eslam et al, 2020; Huang et al, 2021). NAFLD is recently referred to as metabolic-associated fatty liver disease (MAFLD), which includes extrahepatic complications, such as obesity, type 2 diabetes, and cardiovascular and cardiac diseases (Eslam et al, 2020; Liu et al, 2020). Abnormality of hepatic lipid metabolism, including lipogenesis, lipolysis, and fatty acid β-oxidation, links with the occurrence of progressive NAFLD. Lipogenesis is a Bicyclol Plus Berberine Alleviate NAFLD normal synthesis of triglycerides (TG) and fatty acids from acetyl coenzyme A (acetyl-CoA). The abnormal hepatic lipid metabolism is involved in sustained inflammation response and liver injury, further leading to the progression of NAFLD (Dong et al, 2021; Orabi et al, 2021). Apart from the aberrant hepatic lipid metabolism, gut microbiome-mediated alteration of immunity, inflammation, and metabolism are involved in the regulation of NAFLD (He et al, 2021)

Methods

Results

Conclusion