Commentary
Lanifibranor is a moderately potent and well-balanced modulator of the three PPAR isotypes and has a good safety profile. Beneficial effects of lanifibranor on NASH histology, including reduced fibrosis, were confirmed recently in a preclinical model of NASH and fibrosis (choline-deficient amino acid-defined HFD mouse model).
Interestingly, decreased macrophage infiltration in the liver has been observed upon lanifibranor treatment, suggesting that Kupffer cells may be important targets of lanifibranor to improve NAFLD.
Similar results of NASH histology were obtained in the Western diet model, together with a reduction in plasma TG levels.
Lanifibranor is also effective in reducing collagen deposition and increasing plasma adiponectin in mice with CCl4-induced liver fibrosis.
In vitro results have demonstrated that lanifibranor inhibits the proliferation and activation of HSCs, as well as the activation of hepatic macrophages. The anti-inflammatory and anti-fibrotic effects of lanifibranor were also demonstrated in preclinical mouse models of skin and pulmonary fibrosis.
In a relatively near future, the results of clinical trials will determine the therapeutic potential of these novel compounds in NAFLD. Given the role of PPARs in multiple pathways involved in NAFLD and the beneficial effects of each single isotype agonist, PPARs as a promising approach for NAFLD treatment because of potential optimization of the benefits and reduction of the side effects.
