Environmental and genetic determinants of fatty liver in humans

Non-alcoholic fatty liver represents one of the most prevalent conditions affecting about one third of the general population in the Western world, and its prevalence is continuously increasing parallel to the epidemics of obesity. Non-alcoholic fatty liver is a strong predictor of non-alcoholic steatohepatitis, but also of cirrhosis, end-stage liver disease and hepatocellular carcinoma. In recent years, non-alcoholic fatty liver (in addition to overall and visceral obesity) has emerged as a risk factor for insulin resistance, hypertension, dyslipidemia, cardiovascular events and type 2 diabetes. This review summarizes the information currently available about the mechanisms involved in liver fat accumulation (e.g. hepatic lipid supply, de novo lipogenesis, lipid oxidation and the packaging and secretion of triglycerides in the form of very-low-density lipoproteins). New aspects concerning mechanisms potentially leading to a 'dissociation' of fatty liver and insulin resistance are also discussed. Understanding the pathogenesis of fatty liver and its complications, including the identification of new factors secreted from the liver under excess fat accumulation that are involved in the regulation of metabolism ('hepatokines'), is crucial in order to develop and implement efficient prevention and treatment strategies.