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Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis.

Liu HX, Hu Y, French SW, Gonzalez FJ, Wan YJ - Oncotarget (2015)

Bottom Line: The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα(PAC).Forced FGF21 expression in partial hepatectomized hPPARα(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass.In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.

ABSTRACT
Peroxisome proliferator activated receptor α (PPARα) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARα induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARα affects liver regeneration differentially. PPARα-humanized mice (hPPARα(PAC)) were similar to wild type mice in responding to fasting-induced PPARα signaling. However, these mouse livers failed to regenerate in response to partial hepatectomy (PH). The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα(PAC). The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARα(PAC), which might partially be responsible for impaired proliferation. After PH, hPPARα(PAC) displayed steatosis, necrosis, and inflammation mainly in periportal zone 1, which suggested bile-induced toxicity. Quantification of hepatic bile acids (BA) revealed BA overload with increased hydrophobic BA in hPPARα(PAC). Forced FGF21 expression in partial hepatectomized hPPARα(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.

No MeSH data available.


Related in: MedlinePlus

The induction of PPARα target FGF21 is diminished in PPARα-humanized mice after PHExperiments were performed based on the description in Figure legend 2. PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Fgf21 was studied using qPCR (A). Western blot analysis indicated that FGF21 protein level peaked 1 day after PH in WT livers, but not in hPPARαPAC. The induction of CYP4A14 was found in WT mice after PH, but such induction was absent in hPPARαPAC livers after PH (B). Chromatin immunoprecipitation assays were performed using liver tissues (n=3) from WT and hPPARαPAC mice 0 and 1 day after PH with either PPARα or negative control IgG. The purified DNA fragments were amplified using primers specific for the Fgf21 promoter (C). PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Pgc1a, Acox, Cpt1, Cyp4a10, Cyp4a14 and Pepck were studied using qPCR (D-I). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.
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Figure 5: The induction of PPARα target FGF21 is diminished in PPARα-humanized mice after PHExperiments were performed based on the description in Figure legend 2. PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Fgf21 was studied using qPCR (A). Western blot analysis indicated that FGF21 protein level peaked 1 day after PH in WT livers, but not in hPPARαPAC. The induction of CYP4A14 was found in WT mice after PH, but such induction was absent in hPPARαPAC livers after PH (B). Chromatin immunoprecipitation assays were performed using liver tissues (n=3) from WT and hPPARαPAC mice 0 and 1 day after PH with either PPARα or negative control IgG. The purified DNA fragments were amplified using primers specific for the Fgf21 promoter (C). PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Pgc1a, Acox, Cpt1, Cyp4a10, Cyp4a14 and Pepck were studied using qPCR (D-I). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.

Mentions: FGF21 plays a key role in regulating fatty acid oxidation, triglyceride clearance, and ketogenesis in the liver [11]. Fgf21 mRNA level was induced and peaked in WT mice 1 day after PH. In contrast, Fgf21 mRNA was not detected in hPPARαPAC mouse livers after PH (Fig. 5A). Consistent finding was noted at the protein level (Fig. 5B). In addition, the induction of CYP4A14 protein was observed in WT mice, but not detectable in hPPARαPAC livers after PH (Fig. 3B). Moreover, the binding of PPARα in the promoter region of the Fgf21 gene was enriched in WT mouse regenerating livers, but not in hPPARαPAC mice as demonstrated by ChIP-qPCR (Fig. 5C). FGF21 induces PGC1α and its target genes in response to starvation [21]. To further assess the role of FGF21 in liver regeneration, the expression of FGF21 target genes involved in lipid homeostasis (Pgc1a, Acox1, Cpt1, Cyp4a14, Cyp4a10, Pepck) was studied (Fig. 5D-I). In WT mice, the induction of these mRNAs correlated with the observed induction of Fgf21 mRNA 1 day post-PH. There was no induction of the aforementioned genes in hPPARαPAC livers up to 7 days after PH. Cyp4a10 and Cyp4a14 mRNA was not detectable in hPPARαPAC mouse livers.


Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis.

Liu HX, Hu Y, French SW, Gonzalez FJ, Wan YJ - Oncotarget (2015)

The induction of PPARα target FGF21 is diminished in PPARα-humanized mice after PHExperiments were performed based on the description in Figure legend 2. PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Fgf21 was studied using qPCR (A). Western blot analysis indicated that FGF21 protein level peaked 1 day after PH in WT livers, but not in hPPARαPAC. The induction of CYP4A14 was found in WT mice after PH, but such induction was absent in hPPARαPAC livers after PH (B). Chromatin immunoprecipitation assays were performed using liver tissues (n=3) from WT and hPPARαPAC mice 0 and 1 day after PH with either PPARα or negative control IgG. The purified DNA fragments were amplified using primers specific for the Fgf21 promoter (C). PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Pgc1a, Acox, Cpt1, Cyp4a10, Cyp4a14 and Pepck were studied using qPCR (D-I). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496390&req=5

Figure 5: The induction of PPARα target FGF21 is diminished in PPARα-humanized mice after PHExperiments were performed based on the description in Figure legend 2. PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Fgf21 was studied using qPCR (A). Western blot analysis indicated that FGF21 protein level peaked 1 day after PH in WT livers, but not in hPPARαPAC. The induction of CYP4A14 was found in WT mice after PH, but such induction was absent in hPPARαPAC livers after PH (B). Chromatin immunoprecipitation assays were performed using liver tissues (n=3) from WT and hPPARαPAC mice 0 and 1 day after PH with either PPARα or negative control IgG. The purified DNA fragments were amplified using primers specific for the Fgf21 promoter (C). PH was performed in WT and hPPARαPAC mice and hepatic gene expression of Pgc1a, Acox, Cpt1, Cyp4a10, Cyp4a14 and Pepck were studied using qPCR (D-I). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.
Mentions: FGF21 plays a key role in regulating fatty acid oxidation, triglyceride clearance, and ketogenesis in the liver [11]. Fgf21 mRNA level was induced and peaked in WT mice 1 day after PH. In contrast, Fgf21 mRNA was not detected in hPPARαPAC mouse livers after PH (Fig. 5A). Consistent finding was noted at the protein level (Fig. 5B). In addition, the induction of CYP4A14 protein was observed in WT mice, but not detectable in hPPARαPAC livers after PH (Fig. 3B). Moreover, the binding of PPARα in the promoter region of the Fgf21 gene was enriched in WT mouse regenerating livers, but not in hPPARαPAC mice as demonstrated by ChIP-qPCR (Fig. 5C). FGF21 induces PGC1α and its target genes in response to starvation [21]. To further assess the role of FGF21 in liver regeneration, the expression of FGF21 target genes involved in lipid homeostasis (Pgc1a, Acox1, Cpt1, Cyp4a14, Cyp4a10, Pepck) was studied (Fig. 5D-I). In WT mice, the induction of these mRNAs correlated with the observed induction of Fgf21 mRNA 1 day post-PH. There was no induction of the aforementioned genes in hPPARαPAC livers up to 7 days after PH. Cyp4a10 and Cyp4a14 mRNA was not detectable in hPPARαPAC mouse livers.

Bottom Line: The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα(PAC).Forced FGF21 expression in partial hepatectomized hPPARα(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass.In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.

ABSTRACT
Peroxisome proliferator activated receptor α (PPARα) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARα induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARα affects liver regeneration differentially. PPARα-humanized mice (hPPARα(PAC)) were similar to wild type mice in responding to fasting-induced PPARα signaling. However, these mouse livers failed to regenerate in response to partial hepatectomy (PH). The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα(PAC). The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARα(PAC), which might partially be responsible for impaired proliferation. After PH, hPPARα(PAC) displayed steatosis, necrosis, and inflammation mainly in periportal zone 1, which suggested bile-induced toxicity. Quantification of hepatic bile acids (BA) revealed BA overload with increased hydrophobic BA in hPPARα(PAC). Forced FGF21 expression in partial hepatectomized hPPARα(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.

No MeSH data available.


Related in: MedlinePlus