Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription
Cecilia Patitucci, … , Mario Pende, Ganna Panasyuk
Cecilia Patitucci, … , Mario Pende, Ganna Panasyuk
Published April 10, 2017
Citation Information: J Clin Invest. 2017;127(5):1873-1888. https://doi.org/10.1172/JCI90327.
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Research Article Hepatology Oncology

Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription

Abstract

Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPARγ promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPARγ in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1α (HNF1α) and PPARγ, transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1α, thus relieving the suppression of hepatic PPARγ expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPARγ is therapeutically effective in a preclinical murine model of steatosis-associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1α and PPARγ.

Authors

Cecilia Patitucci, Gabrielle Couchy, Alessia Bagattin, Tatiana Cañeque, Aurélien de Reyniès, Jean-Yves Scoazec, Raphaël Rodriguez, Marco Pontoglio, Jessica Zucman-Rossi, Mario Pende, Ganna Panasyuk

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Figure 7

PPARγ inhibition by SR2595 significantly improves the phenotype of tumoral Pten mutants.

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PPARγ inhibition by SR2595 significantly improves the phenotype of tumor...
(A) Blood glucose levels measured during treatment with SR2595 or placebo from 5 to 6 months of age in random-fed Pten LKO male mice. Data are means ± SEM, n = 3. *P < 0.05 vs. D0; #P < 0.05 vs. Pten LKO/placebo; 1-way ANOVA with Tukey’s multiple-comparisons test. (B and C) Hepatic triglycerides (B) and representative images of immunohistochemical analyses with anti-BrdU/anti–β-catenin antibodies and quantification of hepatocyte proliferation presented as a ratio of BrdU+ nuclei to total number of hepatocyte nuclei (C) in livers of random-fed mice treated as in A. Data are means ± SEM, n = 3. *P < 0.05 vs. WT; #P < 0.05 vs. Pten LKO/placebo; 1-way ANOVA with Tukey’s multiple-comparisons test. Arrowheads point to BrdU+ proliferating hepatocytes. The inset shows the magnified view of the BrdU+ hepatocytes. Scale bar: 100 μm. (D) Blood glucose levels measured during treatment with SR2595 from 11 to 12 months of age in random-fed Pten LKO male mice. Data are means ± SEM, n = 6. *P < 0.05 vs. placebo; 2-tailed, unpaired Student’s t test. (E and F) Representative images of livers (E) and H&E-stained liver sections (F) of mice treated as in D. Dashed line marks tumoral area (T) and nontumoral area (NT) of the section. Graph represents the quantification of relative area of adenoma, abnormally proliferating bile ducts, and tumor lesions. Data are means ± SEM, n = 50 lesions per group. *P < 0.05 vs. placebo; 2-tailed, unpaired Student’s t test. Scale bar: 1 cm (E), 100 μm (F).