2. Academic Validation
  3. Combined ASBT Inhibitor and FGF15 Treatment Improves Therapeutic Efficacy in Experimental Nonalcoholic Steatohepatitis

Combined ASBT Inhibitor and FGF15 Treatment Improves Therapeutic Efficacy in Experimental Nonalcoholic Steatohepatitis

  • Cell Mol Gastroenterol Hepatol. 2021;12(3):1001-1019. doi: 10.1016/j.jcmgh.2021.04.013.
David J Matye 1,  Huaiwen Wang 2,  Wenyi Luo 3,  Rachel R Sharp 4,  Cheng Chen 5,  Lijie Gu 5,  Kenneth L Jones 4,  Wen-Xing Ding 6,  Jacob E Friedman 5,  Tiangang Li 7
Affiliations

Affiliations

  • 1 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
  • 2 Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 3 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 4 Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Harold Hamm Diabetes Center, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 5 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 6 Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
  • 7 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: [email protected].
PMID: 33965587 DOI: 10.1016/j.jcmgh.2021.04.013
Abstract

Background & aims: Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether 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 reuptake 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.

Conclusions: 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 whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.

Keywords

Bile Acids; CYP7A1; Fatty Liver; Liver Fibrosis; NASH.

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