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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 3

HFrD activates the proapoptotic branch of the UPR in Chrebp–/– mouse liver.

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HFrD activates the proapoptotic branch of the UPR in Chrebp–/– mouse liv...
(A) Comparable levels of ER stress in the livers of regular chow–fed Chrebp–/– mice and their WT littermates. Livers of 8-week-old male Chrebp–/– mice and their WT littermates (n = 3) on a regular chow diet were subjected to Western blotting for ER stress markers. (B) HFrD feeding activated the proapoptotic branch of the UPR in Chrebp–/– mouse livers. Male and female Chrebp–/– mice and their WT littermates were fed a 70% HFrD for 2 weeks before dissection (n = 4 for WT, n = 6 for Chrebp–/– mice). Protein levels of components of adaptive and proapoptotic branches of ER stress in the liver were assessed with Western blotting (protein level quantification is shown in Supplemental Figure 8). WCL, whole-cell lysate. (C–G) Administration of the chemical chaperone 4-BPA protected Chrebp–/– mice from HFrD-induced liver injury. (C) Male 8-week-old Chrebp–/– mice were pretreated with 4-PBA (1 g/kg BW/day) or PBS by oral gavage for 2 days (n = 3/group), followed by 8 days of HFrD feeding plus 4-PBA or PBS gavage. Liver injury was determined by (D) H&E staining, (E) TUNEL staining (apoptotic cells are indicated by arrowheads), (F) ALT assay, and (G) Western blotting for apoptotic markers. (H–L) Blocking the proapoptotic branch of the UPR protected Chrebp–/– mice from HFrD-induced liver injury. (H) Male and female 8-week-old Chrebp–/– mice were injected with either Chop-knockdown adenovirus (Ad-shChop, n = 6) or control adenovirus (Ad-shLacZ, n = 3) and then fed a HFrD for 2 weeks. Liver injury was assessed by (I) H&E staining, (J) TUNEL staining (apoptotic cells are indicated by arrowheads; original magnification, ×200), (K) ALT assay, and (L) Western blotting for apoptotic markers. *P < 0.05, by 2-tailed Student’s t test. Data represent the mean ± SEM. Scale bars: 100 μm.
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