Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids

Abstract

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance-wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-13 C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2′-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.nonalcoholic fatty liver disease | hepatic insulin resistance | lipogenesis | esterification | mass spectrometry

Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

“…Operating in the short term, this mechanism would promote appropriate energy diversion and storage in adipose tissue. Operating in the long term, it is thwarted by continued substrate (fatty acid)-driven lipogenesis, which occurs in an insulin-independent manner (39). This in turn will result in decreased insulinstimulated net hepatic glycogen synthesis which in turn will promote decreased insulin suppression of hepatic glucose production and postprandial hyperglycemia.…”

Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice

“…Plasma insulin was determined by radioimmunoassay (EMD Millipore), and plasma fatty acids were measured using a Cobas-Roche Analyzer and a spectrophotometric NEFA detection reagent (Wako Diagnostics). Fecal fatty acid levels and profiles were measured as methyl ester derivatives by GC-MS following extraction from feces with chloroform-methanol (1:1) plus an internal deuterated potassium palmitate standard (7,7,8,8-D4; Cambridge Isotopes) and treatment with methanolic borane (48). Liver and heart triglycerides were determined using the Triglyceride SL detection reagent following tissue homogenization and lipid extraction in chloroform-methanol (2:1), followed by acidification with H 2SO4 and phase separation by centrifugation.…”

“…PARK2 mutations resulting in ARJP typically lead to loss of E3 ligase activity and commonly occur within the COOH-terminal RING-finger or IBR domains (9). PARK2 acts as a multifunctional E3 ligase in that it cooperates with several E2 conjugating enzymes, such as UBCH7, UBCH8, and UBCH13/UEV1, and catalyzes mono-and polyubiquitination with Lys 48 and Lys 63 linkages, indicating proteasome-dependent and -independent effects of PARK2-mediated ubiquitination (9,11,17,41,53). Multiple PARK2 substrates have been reported, but it still remains unclear how loss of PARK2 E3 ligase activity contributes to the pathogenesis of ARJP (10).…”

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

“…Efforts to explain this paradox have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge. Vatner et al hypothesized that hepatic triglyceride synthesis could be driven by substrate (fatty acids), independent of changes in hepatic insulin signaling (109). They tested this in awake normal rats, high-fat-fed, insulin-resistant rats and insulin receptor 2′-O-methoxyethyl chimeric antisense oligonucleotide-treated rats infused with varying concentrations of lipid and insulin.…”