The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-alpha agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-alpha activities in counteracting dietary-induced liver fibrosis, we used a PPAR-alpha mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-alpha in acute and chronic models of inflammation were used to study PPAR-alpha's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-alpha inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. Conclusion: The transrepression activity of PPAR-alpha on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-alpha agonists, selectively modulating PPAR-alpha transrepression activity, could thus be an option to prevent NASH and fibrosis progression

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Recently, Pawlak et al, using a pharmacological approach, showed that activation of PPARa inhibited hepatic inflammation and the transition from steatosis toward NASH through a direct, anti-inflammatory mechanism independent of its lipid handling properties (Pawlak et al, 2014). These findings highlight the potential of novel therapeutic strategies to limit the progression of chronic inflammatory liver diseases initiated by metabolic perturbations.…”

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…insight.92264DS1). GO term enrichment of gene clusters pointed at pathways known to be altered in liver diseases (Supplemental Figure 1B and Supplemental Table 1), such as ECM deposition, immune response, regulation of transcription, and nuclear receptors, including the PPARα pathway recently shown to be involved in liver inflammation and fibrosis in humans and rodents (35,36). However, this unsupervised learning-based clustering strategy did not yield a clear-cut patient grouping according to biological or histological parameters, probably reflecting the diverse biological status of patients at the time of biopsy.…”

“…(B) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) plasma level in CCl 4 -treated WT or Dpt -/-mice. Mice (n = 9) were treated biweekly for the indicated period (28 or 49 days) with CCl 4 , and liver enzymes were assayed as described (36). Data are expressed as the mean ± SEM of enzymatic units/L (U/l) and were compared using a 2-tailed t test (n = 8-9).…”

“…Diets were then supplemented with 0.2% Wy14,643, a synthetic PPARα agonist, for 5 days. RNAs were extracted and analyzed by RT-PCR as described (36). Results are expressed relative to a control value arbitrarily set to 1 (CD) and are the mean ± SEM (n = 7).…”

An oxidative stress paradox: time for a conceptual change?

“…These findings suggest that altered H 2 O 2 signalling pathways in HGKO mice delay the onset of fibrosis in NASH. Importantly, the HGKO mouse is yet another model showing that NASH and fibrosis progression can occur separate from changes in steatosis, as also previously shown using peroxisome proliferatoractivated receptor (PPAR)α signalling models [13]. It will be important to study the relative contribution of insulin vs other signalling pathways to the effects of GPX1-induced H 2 O 2 on NASH.…”