Omega-3 Polyunsaturated Fatty Acids in the Treatment of Non-Alcoholic FattyLiver Disease: Are They So Good?

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent hepatic problem in Western and Asian countries where it can affect more than 30% of people [1]. NAFLD pathological characteristic is a fat infiltration of the hepatocytes (hepatic steatosis) in subjects who are mild or no alcohol drinkers and do not have other secondary causes of hepatic lipid accumulation. In one fifth of affected patients, NAFLD can evolve in a liver inflammatory damage, which is associated with oxidative stress, cytolysis, and fibrosis (steatohepatitis) [2]. Of these patients, more than one-third progress to liver cirrhosis and a small part can develop hepatocarcinoma along years. It’s not clear why some patients with NAFLD evolve to non-alcoholic steatohepatitis (NASH) while others remain stable over years, though a role of intestinal inflammation, gut dysbiosis, and hypovitaminosis D has been recently proposed [3]. Consistently, subjects at high risk to develop NAFLD are those affected by obesity, type 2 diabetes mellitus, and other conditions associated with insulin resistance or hyperinsulinemia such as hypertension, dyslipidemia, polycystic ovary disease, and metabolic syndrome, as well as patients with chronic inflammatory bowel diseases [4]. Patients with NAFLD are characterized by increased circulatory levels of triglycerides and free fatty acids (FFAs) that come from the adipose tissue through the lipolytic process, from the hepatic lipid de-novo synthesis, and to a minor extent from food intake. Both insulin resistance and hyperinsulinemia in predisposed subjects are associated with a visceral fat distribution and are responsible for the high level of circulatory FFAs [5]. FFAs enter and accumulate in insulin-resistant hepatocytes and by esterification with glycerol increase hepatic triglycerides synthesis and very low-density lipoproteins (VLDL) production; thus, favoring hypertriglyceridemia. The overflow of plasma lipids and lipid metabolites in non-adipose tissues induces “lipotoxicity”, a pathological process characterized by lipids accumulation in liver and in other organs such as heart, kidney, pancreas, and skeletal muscle [6]. This process is responsible for the development and progression of heart and kidney failure, obesity, and diabetes, as well as for the systemic release of inflammatory cytokines. System cytokines maintain chronic subclinical inflammation, induce oxidative stress and endothelial dysfunction, and predispose to the atherosclerotic process [7]. Although NAFLD has been considered as the hepatic manifestation of the metabolic syndrome, evidence has shown that NAFLD is associated with cardiovascular morbidity and mortality independently of metabolic syndrome. Therefore, other than pro-cirrhotic, NAFLD had to be considered an important modifiable risk factor for cardiovascular diseases [8].