Intermittent fasting-induced autophagy normalization confers hepatic protection in metabolic dysfunction-associated fatty liver disease: Mechanistic insights and implications

Summary. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver condition that can progress to steatohepatitis, cirrhosis, and even liver cancer. Macroautophagy (hereinafter referred to as autophagy) is a pro-survival mechanism that facilitates the lysosomal clearance of damaged organelles, abnormal proteins, and excess lipids. A growing body of evidence indicates that autophagy dysfunction and reduced autophagic flux play critical roles in the pathogenesis of MAFLD. Therefore, restoring autophagy in MAFLD may help reduce steatosis and prevent disease progression. Intermittent fasting (IF), involving periods of restricted to no food intake alternating with periods of regulated/free eating, has been demonstrated to have beneficial effects on body composition, glucose regulation, lipid profiles, and liver function in studies involving both animal models of MAFLD and human subjects. Studies involving individuals with obesity and MAFLD have shown that Ramadan intermittent fasting (RIF), an Islamic religious practice that involves abstaining from food and water intake from sunrise to sunset over approximately 30 consecutive days, significantly reduces body weight, BMI, fat mass, and inflammatory markers while improving liver function and steatosis. The hepatoprotective effects of RIF are associated with the enhanced expression of autophagy-related genes and the restoration of autophagic flux. This upregulation of autophagy as a result of RIF makes it a potentially promising therapeutic strategy for MAFLD. This review summarizes various forms of IF, the mechanisms of autophagy, and evidence of autophagy dysfunction in MAFLD. It also explores how IF, specifically RIF, may normalize autophagy, reduce hepatic steatosis, and improve liver function in human subjects.