Ameliorating effects of melatonin on high-fat diet induced non-alcoholic fatty liver diseases and their associated pathologies: A comprehensive review

Abstract

Non-alcoholic fatty liver disease (NAFLD) is caused by hepatic fat accumulation with a high prevalence globally, especially in Western countries in which individuals have excessive fat consumption. Prolonged intake of high dietary fat causes various diseases due to the imbalance of energy metabolism, which leads to obesity and other pathological conditions. Currently, the exact pathogenesis of NAFLD is still obscure. In this review, the potential etiologies for NAFLD will be discussed, including adipose tissue dysfunction, intrahepatic de novo lipogenesis, hepatic fat accumulation, insulin resistance, hepatic inflammation, inflammasome activation, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress. Melatonin is a potent antioxidant and anti-inflammatory molecule. It is also a regulator of lipid and glucose metabolism which is indicated by melatonin’s effects on weight loss, reduction of liver weight, blood levels of lipids, glucose and insulin, activities of hepatic enzymes, steatohepatitis, and fibrosis. Melatonin considerably reduces mitochondrial dysfunction and proinflammatory cytokines. Moreover, it downregulates NLRP3 and its associated downstream effectors of caspase-1, IL-1β, and IL-18 proteins. This review will update the molecular mechanisms behind high-fat diet induced hepatic dysfunction and the protective role of melatonin in NAFLD.

Experimental Data on the Role of Melatonin in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…The processes underlying NAFLD pathogenesis remain unknown [ 49 ]. It is known that the pathogenetic mechanisms of hepatic steatosis are generally related to either increased delivery of fatty acids to the liver or defects in the complex process of very-low-density lipoprotein (VLDL) synthesis and export of triglycerides [ 3 ].…”

“…The hypothesis was proposed by Tilg and Moschen [ 54 ], according to which hepatic inflammation in NASH is the result of many parallel-acting hits (multiple parallel-hits hypothesis). The latter includes a number of extrahepatic (pro-inflammatory gut microbes, addipose tissue insulin resistance) and intrahepatic stressors (oxidative stress of the liver, stress of the endoplasmic reticulum) [ 49 , 52 ]. About ten years later, Tilg, Adolph, and Moschen [ 55 ] made a critical review of this hypothesis, according to which, in addition to lipotoxicity of adipose tissue and changes in gut microbial functions, other “hits” with anti-inflammatory potential (e.g., dietary, genetic) are also likely to contribute to the inflammation and fibrosis in NAFLD.…”

“…A number of experimental studies have studied the role of melatonin in different parts of the pathogenesis of NAFLD. In a comprehensive review from 2023, Ghosh et al [ 49 ] disscussed the various potential factors that play a role in the pathogenesis of NAFLD (for example, high-fat diet, adipose tissue dysfunction, intrahepatic de novo lipogenesis, hepatic fat accumulation, insulin resistance, hepatic inflammation and inflammasome activation, mitochondrial dysfunction, oxidative stress, etc.) and the possible ameliorative effects of melatonin.…”