Etiopathogenesis of nonalcoholic steatohepatitis: role of obesity, insulin resistance and mechanisms of hepatotoxicity

Abstract

Incidence of nonalcoholic fatty liver disease is increasing with an estimated prevalence of 20-30% in developed nations. This is leading to increased incidence of chronic liver disease, cirrhosis, and hepatocellular cancer. It is critical to understand the etiology and pathogenesis of any disease to create therapeutic targets and develop new treatments. In this paper we discuss the etiology and pathogenesis of nonalcoholic steatohepatitis with special focus on obesity, role of insulin resistance, and molecular mechanisms of hepatotoxicity.

Figure 1

Lipid metabolism in liver. Liver FFA pool is derived from uptake of circulating FFAs and de novo synthesis. The FFAs are then either oxidized or esterified into triglycerides. Triglycerides are then released into circulation as VLDL or stored as vacuoles leading to hepatic steatosis.

Figure 2

Reference [74]. FFA may activate several signaling pathways of apoptosis including upregulation and increased number of death receptors such as Fas and TRAIL receptor 5 (DR5), at the level of the plasma membrane, lysosomal permeabilization, and ER stress both coupled to mitochondrial dysfunction resulting in activation of the mitochondrial pathway of apoptosis. These toxic fatty acids may also activate TLR4 signaling resulting in up-regulation of several pro-inflammatory cytokines. Finally, other lipid types such as free cholesterol (FC) and ceramide may induce mitochondrial dysfunction and activate the mitochondrial pathway of apoptosis. Abbreviations: FFA: free fatty acids; SFA: saturated fatty acids. MUFA: monounsaturated fatty acids, FC: free cholesterol, CE. cholesteryl-ester; ER: endoplasmic reticulum.

Figure 3

Development and progression of nonalcoholic fatty liver disease.  Abbreviations: tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), I-kappa-B-kinase-β (IKKβ), nuclear-factor-kappa-B (NF-κB), Jun N-terminal kinase (JNK), and free fatty acids (FFAs).