Endoplasmic Reticulum Stress Promotes LIPIN2-Dependent Hepatic Insulin Resistance

Abstract

OBJECTIVEDiet-induced obesity (DIO) is linked to peripheral insulin resistance—a major predicament in type 2 diabetes. This study aims to identify the molecular mechanism by which DIO-triggered endoplasmic reticulum (ER) stress promotes hepatic insulin resistance in mouse models.RESEARCH DESIGN AND METHODSC57BL/6 mice and primary hepatocytes were used to evaluate the role of LIPIN2 in ER stress-induced hepatic insulin resistance. Tunicamycin, thapsigargin, and lipopolysaccharide were used to invoke acute ER stress conditions. To promote chronic ER stress, mice were fed with a high-fat diet for 8–12 weeks. To verify the role of LIPIN2 in hepatic insulin signaling, adenoviruses expressing wild-type or mutant LIPIN2, and shRNA for LIPIN2 were used in animal studies. Plasma glucose, insulin levels as well as hepatic free fatty acids, diacylglycerol (DAG), and triacylglycerol were assessed. Additionally, glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed to evaluate the metabolic phenotype of these mice.RESULTSLIPIN2 expression was enhanced in mouse livers by acute ER stress–inducers or by high-fat feeding. Transcriptional activation of LIPIN2 by ER stress is mediated by activating transcription factor 4, as demonstrated by LIPIN2 promoter assays, Western blot analyses, and chromatin immunoprecipitation assays. Knockdown of hepatic LIPIN2 in DIO mice reduced fasting hyperglycemia and improved hepatic insulin signaling. Conversely, overexpression of LIPIN2 impaired hepatic insulin signaling in a phosphatidic acid phosphatase activity–dependent manner.CONCLUSIONSThese results demonstrate that ER stress–induced LIPIN2 would contribute to the perturbation of hepatic insulin signaling via a DAG-protein kinase C ε–dependent manner in DIO mice.

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

“…This is consistent with the fi nding that ethanol-induced hepatic steatosis in Alb-Lpin1 Ϫ / Ϫ mice was not attenuated and actually exacerbated compared with WT control mice ( 33 ). In contrast, acute RNAi-mediated lipin 1 or lipin 2 depletion in liver of mice has been reported to attenuate hepatic steatosis and improve insulin sensitivity ( 12,13 ). Again, it is possible that the lack of effect on these metabolic parameters in Alb-Lpin1…”

“…The regulation of PA and DAG concentrations has potentially important implications for hepatic nutrient homeostasis under conditions of fasting and overnutrition. Indeed, acute RNA interference (RNAi)-mediated depletion of lipin 1 or lipin 2 in mice fed a high-fat diet attenuated hepatic steatosis and led to improvements in hepatic insulin sensitivity ( 12,13 ).…”

Lipin 2 Binds Phosphatidic Acid by the Electrostatic Hydrogen Bond Switch Mechanism Independent of Phosphorylation

“…More specifically, in the liver lipin 2 expression is induced by fasting, diet-induced obesity, and ER stress (6,7). Among the lipin family there are tissues in which expression of more than one lipin isoform occurs, suggesting distinct and overlapping functions.…”

Vibrio vulnificus Secretes an Insulin-degrading Enzyme That Promotes Bacterial Proliferation in Vivo

“…Cells were preincubated in KRBB buffer (25 mM HEPES, pH 7.4, 115 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 25 mM NaHCO 3 ) containing 0.5% BSA for 3 h and stimulated with either 3 (LG) or 15 mM glucose (HG), with or without SidC, for an additional hour as described (18).…”

“…For the intraperitoneal glucose tolerance test (IPGTT), db/db mice were injected intraperitoneally with glucose (1 g/kg of body weight) along with 100 l of either the concentration buffer alone or 1.6 M SidC per mouse. Blood was drawn from the tail vein at the designated times and was used to detect glucose and insulin levels as described previously (18). To determine the effect on insulin and glucose levels in the host after infection of vibrio strains, wild type V. vulnificus MO6 -24/O, ⌬sidC, MO6 -24/O (pRK-sidC), and ⌬crr (pRK-sidC) cells were cultured overnight in LB medium and subcultured into fresh LB …”