The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Abstract

Nonalcoholic fatty liver disease is increasingly regarded as a hepatic manifestation of metabolic syndrome, and the severity of nonalcoholic fatty liver disease seems to increase in parallel with other features of metabolic syndrome. Excess lipid accumulation in the liver cells is not only a mediator of Metabolic Syndrome and indicator of a lipid overload but also accompanied by a range of histological alterations varying from 'simple' steatosis to nonalcoholic steatohepatitis, with time progressing to manifest cirrhosis. Hepatocellular carcinoma may also occur in nonalcoholic steatohepatitis -related cirrhosis with a mortality rate similar to or worse than for cirrhosis associated with hepatitis C. This review summarizes the knowledge about the causal relationship between hepatic fat accumulation, insulin resistance, liver damage and the etiological role of hepatic fat accumulation in pathogenesis of extra- and intra-hepatic manifestations. Special emphasis is given suggestions of new targets treatment and prevention of nonalcoholic fatty liver disease.

Figure 1

Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease (Kerry L. Donnelly, et al, J. Clin. Invest. 2005;115:1343-1351).

Figure 2

Diagram of potential sources of and mechanisms for the accumulation of fat in the liver. Excess caloric intake plays a central role for inducing obesity and thus contributing to insulin resistance. Obesity may additionally impact fat accumulation in the liver by decreasing adiponectin levels and insulin resistance contributes to NAFLD directly by increasing de novo lipogenesis and indirectly by increasing FFA flux to the liver via decreased inhibition of lipolysis. In addition, excess dietary fat intake directly could also contribute to a causal role in hepatic steatosis(modified from Kristina M. The Journal of Clinical Endocrinology & Metabolism 2006; 91: 4753-4761).

Figure 3

Activation of inflammatory signaling pathways by fat(Hepatology. 2008;48:670-8).

Figure 4

Convergence of the FoxO1 and NFκB pathways in IL-1β gene expression: FoxO1 targets at the IRE DNA motif of the IL-1β promoter for trans-activation. This effect along with the activation of the NFκB pathways synergistically promotes macrophage production of proinflammatory cytokine IL-1β. (Dongming Su et al. FoxO1 Links Insulin Resistance to Proinflammatory Cytokine IL-1beta Production in Macrophages. in Press).