Combined ASBT inhibitor and FGF15 treatment improves therapeutic efficacy in experimental non-alcoholic steatohepatitis

Abstract Background & Aims Pharmacological agents targeting bile acid signaling show promise for treating non-alcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This pre-clinical study investigates if combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy. Methods Mice with high fat, cholesterol and fructose (HFCFr) diet-induced NASH and stage-2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice. Results The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid re-uptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings. Conclusion Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate if combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.