FIGURE 9.

Mechanisms for the development of nonalcoholic fatty liver disease (NAFLD) despite hepatic insulin resistance. A: insulin normally activates de novo lipogenesis through sterol regulatory element binding protein 1c (SREBP-1c). B: the seemingly paradoxical coexistence of NAFLD and hepatic insulin resistance has spawned the hypothesis of selective hepatic insulin resistance, wherein insulin activation of lipogenesis is preserved despite impaired insulin regulation of glucose metabolism. However, hepatic de novo lipogenesis has multiple inputs, including ChREBP and mTORC1/SREBP-1c, both of which are activated in states of chronic overnutrition. Additionally, the primary pathway for hepatic triglyceride synthesis is re-esterification of preformed fatty acids, which are readily available in states of chronic overnutrition owing both to dietary supply and to adipose insulin resistance. Even if insulin receptor (INSR) activation of SREBP-1c is impaired by hepatic insulin resistance, these other inputs are likely capable of supporting the lipogenic fluxes that lead to NAFLD. NEFA, nonesterified fatty acid; WAT, white adipose tissue.