The whole transcriptome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice

Abstract

BackgroundThe role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the role of PPARα in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analyzed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on PPARα activation in normal mouse liver, human primary hepatocytes, and human precision cut liver slices.ResultsOf the different human liver models, the gene expression profile of hepatocyte humanized livers most closely resembled actual human liver. In the hepatocyte humanized mouse livers, the human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPARα targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P < 0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPARα targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver.ConclusionThe results support the major role of PPARα in regulating hepatic lipid metabolism, and underscore the more modest effect of PPARα activation on gene regulation in human liver compared to mouse liver. The data suggest that PPARα may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

“…It was assumed that human coactivators/repressors regulate the action of PPAR-α in a humanized way [80,81]. Later, it was shown that PPAR-α activation in human hepatocytes occurred in a more moderate way than in the residual mouse hepatocytes, confirming the abovementioned hypotheses [82].…”

Peripheral sgp130-mediatedtrans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression

“…Analysis of mRNA levels of PPARα target genes in the livers of naïve and fenofibrate treated sgp130Fc and WT mice confirmed the fenofibrate stimulated increase in PPARα activity. Most of the evaluated PPARα target genes in the liver, including Cyp4a10, Cyp4a14, Fabp3, Fatp, L-Fabp and Vnn1 (de la Rosa Rodriguez et al, 2018; Martin et al, 1997; Montagner et al, 2016; van Diepen et al, 2014; Vida et al, 2013), were strongly elevated by fenofibrate (Figure S7); but interestingly, did not have the same effect on Cpt-1 and Apoe (Figure S7). Importantly, fenofibrate treatment reduced the excess body weight (Figure 7B) and gonadal fat pad weight (Figure 7B,C) of sgp130Fc mice, bringing them to levels identical to those of fenofibrate treated WT mice, whose weight was also reduced by about 14 percent in comparison to untreated WT littermate controls.…”

Fat-lowering effects of isorhamnetin are via NHR-49-dependent pathway in Caenorhabditis elegans

“…HADHA, an enzyme that has the enoyl-CoA hydratase and hydroxyacyl-CoA dehydrogenase activities as ECH-1.1 in C. elegans , is responsible for the last three steps of mitochondrial β-oxidation of long chain fatty acids ( Fould et al., 2010 , de la Rosa Rodriguez et al., 2018 ). Consistently, it was reported that daily intake of a PPARα agonist (fenofibrate) upregulated the gene expression of HADHA in humanized liver of chimeric mice after 4 days ( de la Rosa Rodriguez et al., 2018 ). Thus, the upregulation of ech-1.…”