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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

Dysregulated expression of genes involved in bile acid homeostasis in regenerating hPPARαmiceExperiments were performed based on the description in Figure legend 2. Hepatic gene expression of Cyp7a1, Cyp8b1, Cyp27a1, Ntcp, Bsep, and Ostb, were studied using real-time PCR in regenerating WT and hPPARαPAC mouse livers (A-F). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.
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Figure 8: Dysregulated expression of genes involved in bile acid homeostasis in regenerating hPPARαmiceExperiments were performed based on the description in Figure legend 2. Hepatic gene expression of Cyp7a1, Cyp8b1, Cyp27a1, Ntcp, Bsep, and Ostb, were studied using real-time PCR in regenerating WT and hPPARαPAC mouse livers (A-F). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.

Mentions: The expressions of genes encoding proteins that regulate BA homeostasis were then examined. Before PH, hPPARαPAC mice had higher mRNA levels of solute carrier family 10 member 1 (Ntcp), and organic solute transporter beta (Ostb), but similar mRNA levels of Bsep and Cyp7a1/8b1/27a1, as compared to WT mice (Fig. 8A-C). In addition, small heterodimer partner (Shp) mRNA level was more than two folds higher in hPPARαPAC mice compared to WT mice (data not shown). After PH, the mRNA levels of Cyp7a1/8b1/27a1 were suppressed in both genotypes. However the mRNA levels of Cyp7a1/8b1 were barely detectable in hPPARαPAC 1-2 day after PH (Fig. 8A, B). The mRNA levels of Ntcp and Bsep showed similar expression profile in both genotypes, but levels were lower in hPPARαPAC than WT mice 2 days post-PH (Fig. 8D-E). Moreover, Ostb mRNA level was robustly induced by 62-127 fold in hPPARαPAC mice compared with 2-7 fold induction in WT mice post-PH (Fig. 8F).


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)

Dysregulated expression of genes involved in bile acid homeostasis in regenerating hPPARαmiceExperiments were performed based on the description in Figure legend 2. Hepatic gene expression of Cyp7a1, Cyp8b1, Cyp27a1, Ntcp, Bsep, and Ostb, were studied using real-time PCR in regenerating WT and hPPARαPAC mouse livers (A-F). 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 8: Dysregulated expression of genes involved in bile acid homeostasis in regenerating hPPARαmiceExperiments were performed based on the description in Figure legend 2. Hepatic gene expression of Cyp7a1, Cyp8b1, Cyp27a1, Ntcp, Bsep, and Ostb, were studied using real-time PCR in regenerating WT and hPPARαPAC mouse livers (A-F). All values represent mean ± standard deviation, n = 5; * p<0.05, student's t test.
Mentions: The expressions of genes encoding proteins that regulate BA homeostasis were then examined. Before PH, hPPARαPAC mice had higher mRNA levels of solute carrier family 10 member 1 (Ntcp), and organic solute transporter beta (Ostb), but similar mRNA levels of Bsep and Cyp7a1/8b1/27a1, as compared to WT mice (Fig. 8A-C). In addition, small heterodimer partner (Shp) mRNA level was more than two folds higher in hPPARαPAC mice compared to WT mice (data not shown). After PH, the mRNA levels of Cyp7a1/8b1/27a1 were suppressed in both genotypes. However the mRNA levels of Cyp7a1/8b1 were barely detectable in hPPARαPAC 1-2 day after PH (Fig. 8A, B). The mRNA levels of Ntcp and Bsep showed similar expression profile in both genotypes, but levels were lower in hPPARαPAC than WT mice 2 days post-PH (Fig. 8D-E). Moreover, Ostb mRNA level was robustly induced by 62-127 fold in hPPARαPAC mice compared with 2-7 fold induction in WT mice post-PH (Fig. 8F).

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