Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver–alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux‐en‐Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE‐no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE‐NASH‐Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids (P < 0.05), and the glucagon‐alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE‐no steatosis and OBE+steatosis but not in OBE‐NASH‐Fib (median, 7.0; interquartile range, 5.0‐9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Conclusion: Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver–alpha cell may remain in NAFLD despite major improvement in liver histology.