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

Figures

• 

  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.