Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

Abstract

Although commonly associated with obesity, non-alcoholic fatty liver disease (NAFLD) is also present in the lean population representing a unique disease phenotype. Affecting 25% of the world's population, NAFLD is associated with increased mortality especially when progressed to non-alcoholic steatohepatitis (NASH). However, no approved pharmacological treatments exist. Current research focuses mainly on NASH associated with obesity, leaving the effectiveness of promising treatments in lean NASH virtually unknown. This study therefore aimed to evaluate the effect of liraglutide (glucagon-like peptide 1 analogue) and dietary intervention, alone and in combination, in guinea pigs with non-obese NASH. After 20 weeks of high-fat feeding (20% fat, 15% sucrose, 0.35% cholesterol), 40 female guinea pigs were block-randomized based on weight into four groups receiving one of four treatments for 4 weeks: continued high-fat diet (HF, control), high-fat diet and liraglutide treatment (HFL), chow diet (4% fat, 0% sucrose, 0% cholesterol; HFC) or chow diet and liraglutide treatment (HFCL). High-fat feeding induced NASH with severe fibrosis. Liraglutide decreased inflammation (p < 0.05) and hepatocyte ballooning (p < 0.05), while increasing hepatic α-tocopherol (p = 0.0154). Dietary intervention did not improve liver histopathology significantly, but decreased liver weight (p = 0.004), plasma total cholesterol (p = 0.0175), LDL-cholesterol (p = 0.0063), VLDL-cholesterol (p = 0.0034), hepatic cholesterol (p < 0.0001) and increased hepatic vitamin C (p = 0.0099). Combined liraglutide and dietary intervention induced a rapid weight loss, necessitating periodical liraglutide dose adjustment/discontinuation, limiting the strength of the findings from this group. Collectively, this pre-clinical study supports the beneficial effect of liraglutide on NASH and extends this notion to lean NASH.

Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and β-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity

“…We note that NAFLD is also a frequent comorbidity in patients with nonobese patients with T2DM [12]. Additionally, a preclinical trial of GLP-1RA demonstrated decreased liver inflammation and injury in lean patients with nonalcoholic steatohepatitis [41]. Our cohort of normal BMI T2DM patients can be diagnosed as hepatic steatosis because of high LFC, whereas those treated with exenatide exhibited the largest decreases in this parameter after the 24-week intervention.…”

Nonalcoholic Fatty Liver Disease

“…GLP is a peptide derived from the L cells of the lower gastrointestinal tract (the small intestine and proximal colon) and known to enhance insulin secretion from pancreatic β cells and inhibit glucagon release from pancreatic α cells (Campbell and Drucker 2013;Ratziu et al 2015). Whereas the GLP1R agonist exenatide enhanced hepatic steatosis (Tanaka et al 2014), hepatic oxidative stress, and hepatic inflammation (Shao et al 2018) and improved adipose tissue lipolysis in different in vivo models, the application of dulaglutide, lixisenatide, liraglutide, and, recently, semaglutide also shows promising results in terms of improvements in hepatic fat, damage, inflammation, and fibrosis (Armstrong et al 2016;Cusi et al 2018;Ipsen et al 2018;Koutsovasilis et al 2018;Petit et al 2017;Rakipovski et al 2018).…”

Lean non-alcoholic fatty liver disease: Is there a place for novel antidiabetics in the therapeutic management of this underappreciated “enemy”?

“…1 However, there is an outstanding gap in literature regarding the efficacy and safety of pharmacologic agents, in general, and of novel antidiabetics, in specific, for the management of lean NAFLD, except for some sparse experimental data. 8 Thus, based on the aforementioned epidemiologic data, there is an urgent need for well-designed prospective studies enrolling lean NAFLD subjects to investigate the efficacy and safety of the promising novel antidiabetics.…”