Synergistic Regulation of Hepatic Fsp27b Expression by HNF4α and CREBH

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2020 Jun 20

PMID 32553626

Citations 4

Authors

Carlos Ichiro Kasano-Camones

Masayuki Takizawa

Wakana Iwasaki

Shota Sasaki

Mume Hamada

Aoi Morimoto

Masakiyo Sakaguchi

Frank J Gonzalez

Yusuke Inoue

Affiliations

Soon will be listed here.

Abstract

The CIDE (cell death-inducing DFF45-like effector) family composed of CIDEA, CIDEB, CIDEC/FSP27 (fat-specific protein 27), has a critical role in growth of lipid droplets. Of these, CIDEB and CIDEC2/FSP27B are abundant in the liver, and the steatotic livers, respectively. Hepatocyte nuclear factor 4α (HNF4α) has an important role in lipid homeostasis because liver-specific HNF4α-null mice (Hnf4a mice) exhibit hepatosteatosis. We investigated whether HNF4α directly regulates expression of CIDE family genes. Expression of Cideb and Fsp27b was largely decreased in Hnf4a mice, while expression of Cidea was increased. Similar results were observed only in CIDEC2, the human orthologue of the Fsp27b, in human hepatoma cell lines in which HNF4α expression was knocked down. Conversely, overexpression of HNF4α strongly induced CIDEC2 expression in hepatoma cell lines. Furthermore, HNF4α transactivated Fsp27b by direct binding to an HNF4α response element in the Fsp27b promoter. In addition, Fsp27b is known to be transactivated by CREBH that is regulated by HNF4α, and expression of CREBH was induced by HNF4α in human hepatoma cells. Co-transfection of HNF4α and CREBH resulted in synergistic transactivation and induction of Fsp27b compared to that of HNF4α or CREBH alone. These results suggest that HNF4α, in conjunction with CREBH, plays an important role in regulation of Fsp27b expression.

Citing Articles

The facilitating effects of KRT80 on chemoresistance, lipogenesis, and invasion of esophageal cancer.

Yun W, Li J, Yin N, Zhang C, Cui Z, Zhang L Cancer Biol Ther. 2024; 25(1):2302162.

PMID: 38241178 PMC: 10802210. DOI: 10.1080/15384047.2024.2302162.

Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly.

Zhang C, Zhang R, Zhang L, Wang Z, Sun H, Cui Z World J Gastroenterol. 2023; 29(35):5104-5124.

PMID: 37744296 PMC: 10514755. DOI: 10.3748/wjg.v29.i35.5104.

The promoting effects of GPR176 expression on proliferation, chemoresistance, lipogenesis and invasion of oesophageal cancer.

Yun W, Li J, Yin N, Zhang C, Cui Z, Zhang L J Cancer Res Clin Oncol. 2023; 149(16):14641-14655.

PMID: 37584712 PMC: 10602955. DOI: 10.1007/s00432-023-05256-2.

PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice.

Kasano-Camones C, Takizawa M, Ohshima N, Saito C, Iwasaki W, Nakagawa Y J Biochem. 2023; 173(5):393-411.

PMID: 36779417 PMC: 10433406. DOI: 10.1093/jb/mvad005.

References

Xu X, Park J, So J, Lee A . Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis. Hepatology. 2014; 61(3):857-69. PMC: 4329115. DOI: 10.1002/hep.27371. View

Li J, Ye J, Xue B, Qi J, Zhang J, Zhou Z . Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes. 2007; 56(10):2523-32. DOI: 10.2337/db07-0040. View

Sztalryd C, Brasaemle D . The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862(10 Pt B):1221-1232. PMC: 5595658. DOI: 10.1016/j.bbalip.2017.07.009. View

Langhi C, Baldan A . CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis. Hepatology. 2014; 61(4):1227-38. PMC: 4376564. DOI: 10.1002/hep.27607. View

Morimoto A, Kannari M, Tsuchida Y, Sasaki S, Saito C, Matsuta T . An HNF4α-microRNA-194/192 signaling axis maintains hepatic cell function. J Biol Chem. 2017; 292(25):10574-10585. PMC: 5481564. DOI: 10.1074/jbc.M117.785592. View

Viswakarma N, Yu S, Naik S, Kashireddy P, Matsumoto K, Sarkar J . Transcriptional regulation of Cidea, mitochondrial cell death-inducing DNA fragmentation factor alpha-like effector A, in mouse liver by peroxisome proliferator-activated receptor alpha and gamma. J Biol Chem. 2007; 282(25):18613-18624. DOI: 10.1074/jbc.M701983200. View

Daigo K, Kawamura T, Ohta Y, Ohashi R, Katayose S, Tanaka T . Proteomic analysis of native hepatocyte nuclear factor-4α (HNF4α) isoforms, phosphorylation status, and interactive cofactors. J Biol Chem. 2010; 286(1):674-86. PMC: 3013027. DOI: 10.1074/jbc.M110.154732. View

Hayhurst G, Lee Y, Lambert G, Ward J, Gonzalez F . Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001; 21(4):1393-403. PMC: 99591. DOI: 10.1128/MCB.21.4.1393-1403.2001. View

Ye J, Li J, Liu Y, Li X, Yang T, Ma X . Cideb, an ER- and lipid droplet-associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab. 2009; 9(2):177-90. DOI: 10.1016/j.cmet.2008.12.013. View

10.

Brasaemle D, Dolios G, Shapiro L, Wang R . Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. J Biol Chem. 2004; 279(45):46835-42. DOI: 10.1074/jbc.M409340200. View

11.

Zhou L, Xu L, Ye J, Li D, Wang W, Li X . Cidea promotes hepatic steatosis by sensing dietary fatty acids. Hepatology. 2012; 56(1):95-107. DOI: 10.1002/hep.25611. View

12.

Da L, Li D, Yokoyama K, Li T, Zhao M . Dual promoters control the cell-specific expression of the human cell death-inducing DFF45-like effector B gene. Biochem J. 2005; 393(Pt 3):779-88. PMC: 1360731. DOI: 10.1042/BJ20051027. View

13.

Wang M, Zhao S, Tan M . bZIP transmembrane transcription factor CREBH: Potential role in non-alcoholic fatty liver disease (Review). Mol Med Rep. 2016; 13(2):1455-62. DOI: 10.3892/mmr.2015.4749. View

14.

Inoue Y, Hayhurst G, Inoue J, Mori M, Gonzalez F . Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha ). HNF4alpha regulates ornithine transcarbamylase in vivo. J Biol Chem. 2002; 277(28):25257-65. DOI: 10.1074/jbc.M203126200. View

15.

Kang H, Okamoto K, Kim Y, Takeda Y, Bortner C, Dang H . Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes. 2010; 60(1):177-88. PMC: 3012170. DOI: 10.2337/db10-0628. View

16.

Aibara D, Matsuo K, Yamano S, Matsusue K . Fat-specific protein 27b is regulated by hepatic peroxisome proliferator-activated receptor γ in hepatic steatosis. Endocr J. 2019; 67(1):37-44. DOI: 10.1507/endocrj.EJ19-0296. View

17.

Luebke-Wheeler J, Zhang K, Battle M, Si-Tayeb K, Garrison W, Chhinder S . Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H. Hepatology. 2008; 48(4):1242-50. PMC: 2717709. DOI: 10.1002/hep.22439. View

18.

Inoue Y, Peters L, Yim S, Inoue J, Gonzalez F . Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. J Mol Med (Berl). 2006; 84(4):334-44. DOI: 10.1007/s00109-005-0013-5. View

19.

Matsusue K, Kusakabe T, Noguchi T, Takiguchi S, Suzuki T, Yamano S . Hepatic steatosis in leptin-deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab. 2008; 7(4):302-11. PMC: 2587176. DOI: 10.1016/j.cmet.2008.03.003. View

20.

Aibara D, Matsusue K, Takiguchi S, Gonzalez F, Yamano S . Fat-specific protein 27 is a novel target gene of liver X receptor α. Mol Cell Endocrinol. 2018; 474:48-56. PMC: 6594021. DOI: 10.1016/j.mce.2018.02.006. View