Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

Abstract

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

“…It is possible that a serine other than serine 473 becomes phosphorylated in livers of insulin-resistant mice, or that another pathway becomes activated that bypasses the need for active Akt in stimulating mTORC1. In this regard, Semple, et al (36) studied two humans who are heterozygous for an inactivating mutation in Akt2. These individuals had hyperglycemia and hyperinsulinemia.…”

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

“…Biochemical analyses were performed on blood samples collected after a standardized overnight fast. Insulin, leptin, and adiponectin were measured using customized autoDELFIA immunoassays as previously described (26). Body composition, liver fat, and hepatic de novo lipogenesis were also measured as described previously (26).…”

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

“…Hepatic DNL was measured on the study day, based on the incorporation of 2 H in plasma water (Finnigan GasBench‐II; ThermoFisher Scientific, UK) and into VLDL 1 ‐ and VLDL 2 ‐TG palmitate using gas chromatography–mass spectrometry 27. For simplicity, this is referred to as “%DNL” and represents synthesis of FAs from precursors such as sugars and amino acids 28…”