Hints for Therapeutic Interventions Through Exploring the Effects of Calorie Restriction on NAFLD by Mechanistic Approach

BACKGROUND: The worldwide prevalence and severity of non-alcoholic fatty liver disease are increasing in parallel with the growing obesity epidemic. According to the US Practice Guidelines for the Diagnosis and Management of NAFLD, weight loss interventions based on hypocaloric diets – either alone or in conjugation with physical activity – can reduce hepatic steatosis. Hence, understanding the ways in which calorie restriction affects NAFLD can help in developing optimal treatments. METHOD: In this review study, the main focus was on possibly disturbed pathways in NAFLD, and how calorie restriction may attenuate them. For this purpose, both human and animal studies available through Pubmed were reviewed. RESULTS: Calorie restriction can upregulate energy-sensing pathways, including AMPK/SIRTUIN, and downregulate insulin-signaling pathway IGF1/PI3K/AKT. In NAFLD, AKT is over-activated through the PI3K-active mTOR and FOXO recruitment. Consequences include gluconeogenic and lipogenic enzyme alteration, insulin resistance, autophagy reduction, and liver cells apoptosis, all of which may be inverted through calorie restriction. Moreover, increased mitochondrial biogenesis, reduced inflammation, and increased fatty acid oxidation are mediated through AMPK, SIRTUIN, and PPARS, all of which are altered in NAFLD. CONCLUSION: This review outlines prominent pathways, the targeting of which may be promising for NAFLD treatment, according to evidence-based studies.