Mechanisms leading to liver steatosis. Mechanisms leading to liver steatosis. Insulin resistance, occurring in response to a variety of genetic and acquired factors, is intimately associated with the development of a steatotic liver. At least two mechanisms contribute to exacerbation of insulin resistance by cyclic self-perpetuation: 1) chronic activation of IKKβ, which plays a key role not only in the production of and response to proinflammatory cytokines, such as TNF-α, but also in the development of insulin resistance; and 2) the decreased clearance of insulin that occurs in the presence of a steatotic liver, thus creating a hyperinsulinemic medium that in turn enhances insulin resistance. Serine phosphorylation (rather than tyrosine phosphorylation) of IRS-1 (which leads to disruption of insulin signaling) represents a central step in the stimulation of insulin resistance by a variety of factors. apoB, apolipoprotein B; JNK, c-Jun NH2-terminal kinase; MTTP, microsomal triglyceride transfer protein. Jesús Medina et al. Dia Care 2004;27:2057-2066 ©2004 by American Diabetes Association