The Role of Lipid and Lipoprotein Metabolism in Non-Alcoholic Fatty Liver Disease

Abstract

Due to the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver disorders in children and adolescents. NAFLD comprises a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. The mechanism of the liver injury in NAFLD is currently thought to be a "multiple-hit process" where the first "hit" is an increase in liver fat, followed by multiple additional factors that trigger the inflammatory activity. At the onset of disease, NAFLD is characterized by hepatic triglyceride accumulation and insulin resistance. Liver fat accumulation is associated with increased lipotoxicity from high levels of free fatty acids, free cholesterol and other lipid metabolites. As a consequence, mitochondrial dysfunction with oxidative stress and production of reactive oxygen species and endoplasmic reticulum stress-associated mechanisms, are activated. The present review focuses on the relationship between intra-cellular lipid accumulation and insulin resistance, as well as on lipid and lipoprotein metabolism in NAFLD.

Keywords: lipid metabolism; lipids; nonalcoholic fatty liver disease.

Figure 1

Fatty acid overload in the hepatocyte activates the protein kinase c- epsilon (PKC-ε) and/or c-Jun N-terminal kinase (JNK-1), with subsequent impairment of phosphorylation of the insulin receptor substrate (IRS)-1 and IRS-2. This results in impairment of the insulin signaling pathway. The decreased insulin action on glycogen synthase induces increased glucose secretion. Yet, fat accumulation stimulates neoglucogenesis further increasing the hepatic glucose secretion. The hepatocyte’s attempt to dispose of excessive triglyceride accumulation through increased VLDL secretion, is ineffective, further contributing to accumulation of liver fat. DNL: de novo lipogenesis.

Figure 2

Excess fat accumulation promotes increased “de novo lipogenesis” (DNL) and fatty acid (FA) beta-oxidation. These mechanisms lead to reactive oxygen species (ROS) generation which induces oxidative mitochondrial damage and endoplasmic reticulum (ER) stress. In parallel, the accumulation of free (non-esterified) cholesterol and ceramides enhances both mitochondrial dysfunction and ER stress, and induces the activation of stellate cells as well as Kupffer cells, thus promoting inflammation and fibrosis. Furthermore, tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) from adipose tissue enhance the inflammatory process and promotes ceramide accumulation, contributing to insulin resistance through different pathways. Ultimately, these events trigger the hepatocyte apoptotic pathway, leading to cell death. PKC: protein kinase; CJNK-IRS: c-Jun N-terminal kinase-insulin receptor substrate; PP2A: Protein Phosphatase 2A.