Altered insulin signaling by lipid intermediates

Altered insulin signaling by lipid intermediates. Increased nutrient influx raises intracellular FA concentrations. With nutrient surfeit, elevated malonyl-CoA inhibits CPT-1 and β-oxidation and results in increased availability of acyl-CoAs for TAG synthesis and storage or secretion. Intermediates in the TAG biosynthetic pathway activate inhibitors of insulin signaling, including protein kinase C (PKC), mTOR, and S6K, which suppress IRS-1 activation of PIP3. Ceramide inhibits Akt-mediated insulin signaling, derepressing FOXO and leading to increases in transcription of phosphoenolpyruvate (PEPCK) and glucose-6-phosphatase (G-6-Pase). These enhance gluconeogenesis and hepatic glucose output. Nutrients act on transcription factors (LXR, ChREBP, SREBP-1c and PPAR γ), which increase transcription of genes involved in FA and TAG synthesis (ACC, FAS, GPAT1). These enhance steatosis and hepatic insulin resistance. DHAP, dihydroxyacetone-P; G3P, glycerol-3-P; GSK, glycogen synthase kinase.

Publication

Hepatic triacylglycerol accumulation and insulin resistance. (2009) Cynthia A. Nagle, et al. J Lipid Res. 2009 Apr;50(Suppl):S74-S79. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions