Berberine Ameliorates Metabolic-Associated Fatty Liver Disease Mediated Metabolism Disorder and Redox Homeostasis by Upregulating Clock Genes: Clock and Bmal1 Expressions.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases, which in turn triggers mild inflammation, metabolic dysfunction, fibrosis, and even cancer. Accumulating evidence has suggested that Berberine (BBR) could significantly improve MAFLD progression. Clock and Bmal1 as heterodimer proteins highly participated in the development of MAFLD, but whether BBR targets Clock and Bmal1 in MAFLD remains poorly understood. The result suggested that the protein levels of Clock and Bmal1 were decreased in MAFLD mice, which was negatively correlated with elevated reactive oxygen species (ROS) accumulation, the H2O2 level, liver inflammation, metabolic dysfunction, and insulin resistance. The mRNA and protein levels of Clock and Bmal1 were also decreased in glucosamine-induced HepG2 cells, which were are negatively related to glucose uptake, the ROS level, and the H2O2 level. More importantly, Bmal1 siRNA could mimic the effect of glucosamine in HepG2 cells. Interestingly, Berberine (BBR) could rescue metabolism disorder and redox homeostasis through enhancing Clock and Bmal1 expression in vivo and in vitro. Therefore, BBR might be an effective natural compound for alleviating redox homeostasis, metabolism disorder, and liver pathological changes in MAFLD by activating Clock and Bmal1 expression.