The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease.

Katrine D Galsgaard

doi:10.3390/jcm9124049

Abstract

A key criterion for the most common chronic liver disease—non-alcoholic fatty liver disease (NAFLD)—is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. However, in recent years, glucagon has re-emerged as an important regulator of other metabolic processes including lipid and amino acid/protein metabolism. This review discusses the evidence that in NAFLD, hepatic glucagon resistance may result in a dysregulated lipid and amino acid/protein metabolism, leading to excess accumulation of fat, hyperglucagonemia, and increased oxidative stress contributing to the worsening/progression of NAFLD.

Highlights

Glucagon is encoded by the preproglucagon gene (GCG) [1], expressed in alpha cells, enteroendocrine L-cells, and the brain [2]
GCG is processed by prohormone convertase (PC) 2 yielding glucagon [3], whereas in L-cells, GCG is processed by PC1/3, yielding glucagon-like peptide (GLP)-1, GLP-2, glicentin, and oxyntomodulin [4]
Recent evidence suggests that the processing is not as tissue-specific as previously thought, since PC1/3 may be active in alpha cells, giving rise to pancreatic GLP-1 [5,6,7,8], and PC2 might act in L-cells to create gut-derived glucagon [9,10,11]

Summary

Introduction

Glucagon is encoded by the preproglucagon gene (GCG) [1], expressed in alpha cells, enteroendocrine L-cells, and the brain [2]. Glucagon binds to its receptor, the glucagon receptor, and regulates hepatic glucose, lipid, and amino acid/protein metabolism [20]. 2. The Glucagon Receptor as a Target in the Treatment of Type 2 Diabetes, Obesity, and NAFLD

Results

Conclusion