The molecular basis of hepatic de novo lipogenesis in insulin resistance

Abstract

Humans with obesity and type 2 diabetes exhibit the classic triad of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. The paradox of selective insulin resistance in the liver, in which the gluconeogenic pathway becomes insensitive to insulin but the lipogenesis pathway remains sensitive to insulin, leads to an elevation in hepatic and plasma levels of fatty acids and triglyceride and makes detrimental contributions to the development of insulin resistance. However, the precise mechanism for selective insulin resistance remains largely unknown. AMPactivated protein kinase (AMPK) is an energy sensor that regulates metabolic homeostasis. Recently, elucidating the role of AMPK leads to surprising findings and helps identify novel downstream effectors of AMPK. Cellular and molecular biological approach and obese, diabetic mouse models are utilized to characterize that sterol regulatory element binding protein (SREBP), a family of the transcription regulator of lipid synthesis, functions as a conserved substrate of AMPK. AMPK specifically interacts with and phosphorylates SREBP-1c and SREBP-2. AMPK and its pharmacological activators, such as metformin and polyphenols, inhibit the cleavage processing of SREBP-1c and SREBP-2, decrease the nuclear translocation, and reduce the transcription of target genes involved in the biosynthesis of fatty acid, triglyceride, and cholesterol at least in part through AMPK-dependent inhibition of SREBP in hepatocytes. Strikingly, integrated inhibition of AMPK and stimulation of SREBP are implicated on hepatic lipogenesis and steatosis. In contrast, suppression of the de novo lipogenesis by AMPK in the liver results from an increase in SREBP-1 phosphorylation and a reduction in its cleavage processing and transcriptional activity in insulin resistance. These studies provide mechanistic insight into the development of potential therapeutic strategies to target the nutrient sensing AMPK-SREBP pathway for treating type 2 diabetes and related metabolic disorders.