Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview

Abstract

Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.

Keywords: insulin resistance; metabolic syndrome; molecular mechanisms; nonalcoholic fatty liver disease; pathogenesis; steatosis; therapy.

Figure 1

Multiple-hit pathogenesis of NAFLD [86,110,111]. Genetic factors cooperate with metabolic and environmental factors to promote the accumulation of fat in hepatocytes and successively cause inflammation, cellular death and fibrosis. Anatomically, besides the liver, the main factors are insulin sensitive organs such as adipose tissue and muscle, which respectively produce adipokines and myokines, and also promote inflammation and oxidative stress in the liver. The gut microbiota releasing PAMPs, the bile acid system and the presence of iron deposits contribute to liver damage. Finally, all these mechanisms are modulated by the brain, particularly by circadian rhythm.