Impaired Ca2 + signaling due to hepatic steatosis mediates hepatic insulin resistance in Alström syndrome mice that is reversed by GLP-1 analog treatment

Am J Physiol Cell Physiol. 2021 Jul 1;321(1):C187-C198. doi: 10.1152/ajpcell.00020.2021. Epub 2021 Jun 9.

Abstract

Ca2+ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca2+ regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca2+ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca2+-insulin and insulin-Ca2+ signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca2+ release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca2+ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca2+ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca2+ release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca2+ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca2+ signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.

Keywords: calcium; diabetes; fatty liver; insulin; lipid metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alstrom Syndrome / drug therapy*
  • Alstrom Syndrome / metabolism
  • Alstrom Syndrome / pathology
  • Animals
  • Blood Glucose / metabolism
  • Calcium / metabolism
  • Calcium Signaling
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Exenatide / pharmacology*
  • Fluorescent Dyes / metabolism
  • Fura-2 / metabolism
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism
  • Insulin Resistance
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / pathology
  • Palmitic Acid / pharmacology

Substances

  • Blood Glucose
  • Fluorescent Dyes
  • Hypoglycemic Agents
  • Insulin
  • Palmitic Acid
  • Glucagon-Like Peptide 1
  • Exenatide
  • Calcium
  • Fura-2