The PPARα-FABP1 Axis: A New Target for NASH Therapies?

Although it is known that non-alcoholic steatohepatitis (NASH) increases the risk of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma, no pharmacologic therapy has yet been approved to treat it.
PUBLISHED IN: Hepatology 2023

Comment:

Although it is known that non-alcoholic steatohepatitis (NASH) increases the risk of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma, no pharmacologic therapy has yet been approved to treat it. The surgical risk of bariatric surgery, which has been shown to resolve NASH, justifies research into targets which may serve as the basis of effective drug treatments. The peroxisome proliferator‐activated receptor α (PPARα)-fatty acid‐binding protein 1 (FABP1) axis, responsible for modulating hepatic lipid homeostasis and dietary fat absorption, may be one such target. 

The aim of this study was to investigate the role of the intestinal PPARα-FABP1 axis in the progression of NASH.

Key learnings:

In humans with obesity and in mice fed with a HF diet, intestinal PPARα was activated and FABP1 was upregulated. Additionally, the disruption of intestine-specific Ppara or Fabp1 in HFD-fed mice reduced both NASH and obesity-related metabolic disorders. A PPARα‐specific antagonist, tested for the treatment of obesity and NASH, was further shown to reduce NASH in an intestinal PPARα-dependent manner. However, this effect was found to be mediated by FABP1: intestinal Ppara gene disruption improved obesity and NASH solely depending on the presence of intestinal FABP1. These findings suggest that intestinal PPARα-FABP1 signalling promotes NASH progression through the regulation of dietary fatty acids. Pharmacologic therapies inhibiting intestinal PPARα and particularly FABP1 could thus prove to be effective treatments for NASH.

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S Duarte, BSc

Articles: 103

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