Physcion Protects Against Ethanol-Induced Liver Injury by Reprogramming of Circadian Clock

Abstract

The circadian clock plays a key role in our daily physiology and metabolism. Alcohol consumption disrupts the circadian rhythm of metabolic genes in the liver; however, the potential contribution of circadian clock modulation to alcoholic liver disease (ALD) is unknown. We identified a novel liver protective agent, physcion, which can alleviate fat accumulation and inflammation in ALD mice via reprogramming the hepatic circadian clock. The model of alcoholic hepatitis was established by intragastrically administering ethanol. In vitro, physcion was investigated by treating HepG2 cells with ethanol. The role of circadian clock in Physcion caused liver protection was tested by knocking down the core circadian gene Bmal1. Physcion application caused reduced lipogenesis and alleviated inflammation in alcohol-induced mice. In alcoholic hepatosteatosis models, physcion upregulated the core circadian genes. And the circadian misalignment triggered by ethanol was efficiently reversed by physcion. Physcion attenuated lipogenesis via reprogramming the circadian clock in HepG2 cells. Suppression of Bmal1 by RNA interference abolished the protective of physcion. In addition, Physcion binds to the active pocket of BMAL1 and promotes its expression. The study identified the novel liver protective effects of physcion on alcohol-induced liver injury, and modulation of the core circadian clock regulators contributes to ALD alleviation. More importantly, strategies targeting the circadian machinery, for example, Bmal1, may prove to be beneficial treatment options for this condition.

Effects of Anthraquinones on Immune Responses and Inflammatory Diseases

“…In mice with steato-hepatitis induced by excessive alcohol, physcion attenuated lipid accumulation and inflammation in ALD mice by regulating the Bmal1 (core circadian gene) expression, a process involving AMPK/PPARα-involved fatty acid oxidation. In vitro, the effect of physcion on ethanol treated HepG2 cells was in accordance with that of in vivo [150]. Although AQs show obvious hepato-protective effects, more attention has been paid to the liver injury caused by traditional Chinese herbs containing AQs, such as Radix Polygoni Multiflori and Radix et Rhizoma Rhei.…”

Network pharmacology analysis and molecular docking to unveil the potential mechanisms of San-Huang-Chai-Zhu formula treating cholestasis

“…For instance, emodin can suppress liver injury and bile acids secretion, and exert a protective effect on intrahepatic cholestasis [ 40 ]. Physcion is a novel liver protective agent by reprogramming the hepatic circadian clock [ 41 ]. Rhein may promote bile acid transport and reduce bile acid accumulation in liver [ 42 ].…”

Melatonin Prevents against Ethanol-Induced Liver Injury by Mitigating Ferroptosis via Targeting Brain and Muscle ARNT-like 1 in Mice Liver and HepG2 Cells

“…Growing evidence has disclosed that ethanol could impair the circadian rhythm and trigger robust phase shifts of the circadian clocks and finally contribute to liver injury. 1,31,32 Meanwhile, a growing number of data revealed the strong bond between the recovered circadian clock and melatonin administration. 19,33−35 As the results present in Figure 3A,B, the protein expression of BMAL1 was upregulated and that of Clock was downregulated upon ethanol administration, and melatonin further promoted the expression of BMAL1 and Clock in mice liver and mice primary hepatocytes.…”

“…The excessive intake or abuse of alcohol was shown to trigger certain health problems, including alcoholic-related liver disease (ALD), which is a chief global cause of chronic liver disease. 1 The pathologic process of ALD fluctuates from hepatic steatosis to inflammation and forward progresses to fibrosis, cirrhosis, and so far as hepatocellular carcinoma (HCC) upon long-term alcohol abuse. 2 However, the mechanisms of the pathogenesis of ALD are not yet entirely revealed and the cure for ALD is absent except for liver transplantation in the condition of severe disease states.…”