Commentary
In a CDAA-HFD (choline-deficient, amino acid-defined high-fat diet-induced) model, which induces severe inflammation and liver fibrosis, S. Lefere et al. studied the efficacy of single and pan-PPAR agonists in the treatment of progressive steatohepatitis.
To examine the pathophysiological sequence of steatohepatitis amelioration upon treatment with PPAR agonists, the authors analysed the effects of short-term treatment. PPAR agonists were administered for 2 weeks in mice. Similar to the long-term treatment, lanifibranor reduced grading of steatosis, lobular inflammation and ballooning, and thus the overall NAFLD activity score.
This was accompanied by a significant reduction in hepatic lipid content and expression of inflammatory cytokines in lanifibranor-treated mice. Liver fibrosis was significantly improved by lanifibranor.
Lanifibranor decreased the number of hepatic macrophages already after 2 weeks of treatment. The proportion and absolute number of hepatic pro-inflammatory monocyte-derived macrophages were reduced specifically by lanifibranor compared to the single PPAR agonists and was accompanied by a significant decrease in the overall number of leukocytes. Hepatic monocytes were decreased as well.
