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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 expression profiles of hepatic genesExperiment was performed based on the description in Figure legend 2. Hepatic gene expression of Nrf2, IL-6, MCP1, CK19, αSma and Col1a1 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 9: The expression profiles of hepatic genesExperiment was performed based on the description in Figure legend 2. Hepatic gene expression of Nrf2, IL-6, MCP1, CK19, αSma and Col1a1 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: Inflammatory signaling and fibrotic response were studied due to the occurring pathology in hPPARαPAC mice. The nuclear factor erythroid 2-related factor (Nrf2) was studied for its protective function against oxidative stress. During normal liver regeneration, Nrf2 was induced and peaked 2 days after PH in WT mice. The induction of Nrf2 was absent in hPPARαPAC mice during the first 2 days after PH, indicating impaired regulation of anti-oxidative stress by human PPARα (Fig. 9A). Pro-inflammatory genes including interleukin 6 (Il-6), and membrane cofactor protein 1 (Mcp1) were highly induced in hPPARαPAC mice 1.5 days post-PH in comparison with WT counterparts (Fig. 9B-C). The expression levels of cytokeratin-19 (Ck19), which typically expressed in hepatobiliary tracts, were minimally changed in WT, but markedly elevated in the hPPARαPAC mice post-PH. The expression levels of fibrosis marker α-smooth muscle actin (αSma) and collagen type I, α 1 (Col1a1) also showed higher induction in hPPARαPAC than WT mice after PH (Fig. 9E-F).


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 expression profiles of hepatic genesExperiment was performed based on the description in Figure legend 2. Hepatic gene expression of Nrf2, IL-6, MCP1, CK19, αSma and Col1a1 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 9: The expression profiles of hepatic genesExperiment was performed based on the description in Figure legend 2. Hepatic gene expression of Nrf2, IL-6, MCP1, CK19, αSma and Col1a1 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: Inflammatory signaling and fibrotic response were studied due to the occurring pathology in hPPARαPAC mice. The nuclear factor erythroid 2-related factor (Nrf2) was studied for its protective function against oxidative stress. During normal liver regeneration, Nrf2 was induced and peaked 2 days after PH in WT mice. The induction of Nrf2 was absent in hPPARαPAC mice during the first 2 days after PH, indicating impaired regulation of anti-oxidative stress by human PPARα (Fig. 9A). Pro-inflammatory genes including interleukin 6 (Il-6), and membrane cofactor protein 1 (Mcp1) were highly induced in hPPARαPAC mice 1.5 days post-PH in comparison with WT counterparts (Fig. 9B-C). The expression levels of cytokeratin-19 (Ck19), which typically expressed in hepatobiliary tracts, were minimally changed in WT, but markedly elevated in the hPPARαPAC mice post-PH. The expression levels of fibrosis marker α-smooth muscle actin (αSma) and collagen type I, α 1 (Col1a1) also showed higher induction in hPPARαPAC than WT mice after PH (Fig. 9E-F).

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