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Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity
Deqiang Zhang, … , M. Bishr Omary, Lei Yin
Deqiang Zhang, … , M. Bishr Omary, Lei Yin
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2855-2867. https://doi.org/10.1172/JCI89934.
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Research Article Hepatology Metabolism

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

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Abstract

Epidemiologic and animal studies implicate overconsumption of fructose in the development of nonalcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remain largely unknown. Here, we have presented evidence supporting the essential function of the lipogenic transcription factor carbohydrate response element–binding protein (ChREBP) in mediating adaptive responses to fructose and protecting against fructose-induced hepatotoxicity. In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis. In Chrebp-KO mouse livers, a HFrD reduced levels of molecular chaperones and activated the C/EBP homologous protein–dependent (CHOP-dependent) unfolded protein response, whereas administration of a chemical chaperone or Chop shRNA rescued liver injury. Elevated expression levels of cholesterol biosynthesis genes in HFrD-fed Chrebp-KO livers were paralleled by an increased nuclear abundance of sterol regulatory element–binding protein 2 (SREBP2). Atorvastatin-mediated inhibition of hepatic cholesterol biosynthesis or depletion of hepatic Srebp2 reversed fructose-induced liver injury in Chrebp-KO mice. Mechanistically, we determined that ChREBP binds to nuclear SREBP2 to promote its ubiquitination and destabilization in cultured cells. Therefore, our findings demonstrate that ChREBP provides hepatoprotection against a HFrD by preventing overactivation of cholesterol biosynthesis and the subsequent CHOP-mediated, proapoptotic unfolded protein response. Our findings also identified a role for ChREBP in regulating SREBP2-dependent cholesterol metabolism.

Authors

Deqiang Zhang, Xin Tong, Kyle VanDommelen, Neil Gupta, Kenneth Stamper, Graham F. Brady, Zhuoxian Meng, Jiandie Lin, Liangyou Rui, M. Bishr Omary, Lei Yin

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Figure 1

Loss of Chrebp sensitizes mice to HFrD-induced liver injury.

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Loss of Chrebp sensitizes mice to HFrD-induced liver injury.
Eight-week-...
Eight-week-old WT and Chrebp–/– mice were fed a HFrD (70% calories from free fructose) for two weeks (n = 4 for WT, n = 6 for Chrebp–/– mice). (A–C) Loss of Chrebp blocked HFrD-induced hepatic lipogenesis. After 2 weeks of HFrD feeding, (A) a liver triglyceride (TG) assay and (B) Oil Red O staining were performed to assess lipid accumulation in the livers of Chrebp–/– mice and their WT littermates. (C) Protein levels of lipogenic enzymes were assessed by Western blotting (protein quantification is shown in Supplemental Figure 4G). (D–F) HFrD feeding induced liver injury in Chrebp–/– mice. (D) After H&E staining of livers from Chrebp–/– mice and their WT littermates fed either regular chow or a HFrD, (E) liver injury was scored blindly on a scale of 0 to 2. Mallory-Denk bodies are indicated by yellow arrows. (F) Serum ALT levels were measured at the start and end of HFrD feeding. (G and H) HFrD feeding induced apoptosis in Chrebp–/– mouse livers. Apoptosis was determined by (G) TUNEL staining and (H) Western blotting for apoptotic markers. Apoptotic cells are indicated by arrowheads. (I and J) HFrD feeding increased the expression of PUMA at both (I) mRNA and (J) protein levels. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test; ****P < 0.0001, by 1-way ANOVA with Tukey’s post-hoc test. Data represent the mean ± SEM. Scale bars: 100 μm; original magnification, ×400 (enlarged images in bottom panels of D).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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