Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation

Abstract

Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver), through nonalcoholic steatohepatitis (NASH) to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD), and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.

Figure 1

Lipid and lipoprotein pathways in the pathogenesis of NAFLD. NAFLD is considered to be liver manifestation of obesity and metabolic syndrome. In response to insulin and glucose, transcription factors SREBPs and ChREBP are activated and induce the expression of genes involved in the synthesis of fatty acids and cholesterol in the liver. Enhanced lipogenesis leads to enhanced VLDL production, a major metabolic perturbation in NAFLD. Increased VLDL secretion in plasma results in increase in LDL through CETP-mediated exchange of cholesteryl esters and triglycerides between LDL and VLDL, followed by triglyceride removal from LDL by hepatic lipase (HL). Liver removes LDL from circulation by LDLR-mediated endocytosis. Oxidized LDL and FFA are transported to the liver by CD-36, FA translocase, and scavenger receptor. Italics: metabolic genes, black lines: metabolic pathways, black dash lines: coming out or in the liver, white lines: transcriptional regulation, *process in the mitochondria.

Figure 2

Summary of insulin resistance-induced lipid abnormalities and consequent pathogenesis of NAFLD. In an insulin resistant setting, insulin is unable to inhibit lipolysis in adipose tissue leading to overflow of free FA into the bloodstream and in the liver. In the liver, hyperinsulinemia and hyperglycemia induce the synthesis of fatty acid and cholesterol which results in increased triglyceride synthesis and VLDL assembly and secretion. Since triglyceride synthesis prevails over VLDL secretion, excess triglycerides accumulate and lead to fatty liver development. In NASH, triglyceride synthesis and VLDL assembly is impaired and free FA and cholesterol accumulate. Increased lipid accumulation leads to lipid peroxidation and inflammation which exacerbates liver damage.