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Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis.

ABSTRACT: Fat-specific protein 27 (Fsp27) is a lipid droplet-associated protein that promotes lipid droplet (LD) growth and triglyceride (TG) storage in white adipocytes. Fsp27 is also highly expressed in the steatotic liver and contributes to TG accumulation. In this study we discovered that the liver produces Fsp27?, an alternative Fsp27 isoform, which contains 10 additional amino acids at the N-terminus of the original Fsp27 (Fsp27?). White adipose tissue (WAT) and the liver specifically expressed Fsp27? and Fsp27? transcripts, respectively, which were driven by distinct promoters. The Fsp27? promoter was activated by the liver-enriched transcription factor cyclic-AMP-responsive-element-binding protein H (CREBH) but not by peroxisome proliferator-activated receptor gamma (PPAR?), which activated the Fsp27? promoter. Enforced expression of the constitutively active CREBH strongly induced Fsp27? and the human ortholog CIDEC2 in mouse hepatocytes and HepG2 cells, respectively. In contrast, loss of CREBH decreased hepatic Fsp27? in fasted mice, suggesting that CREBH plays a critical role in Fsp27? expression in the liver. Similar to Fsp27?, Fsp27? localized on the surface of lipid droplets and suppressed lipolysis. Consequently, enforced expression of Fsp27? or CREBH promoted lipid droplet enlargement and TG accumulation in the liver.The CREBH-Fsp27? axis is important for regulating lipid droplet dynamics and TG storage in the liver.

SUBMITTER: Xu X

PROVIDER: S-EPMC4329115 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis.

Xu Xu X Park Jong-Gil JG So Jae-Seon JS Lee Ann-Hwee AH

Hepatology (Baltimore, Md.) 20150128 3

<h4>Unlabelled</h4>Fat-specific protein 27 (Fsp27) is a lipid droplet-associated protein that promotes lipid droplet (LD) growth and triglyceride (TG) storage in white adipocytes. Fsp27 is also highly expressed in the steatotic liver and contributes to TG accumulation. In this study we discovered that the liver produces Fsp27β, an alternative Fsp27 isoform, which contains 10 additional amino acids at the N-terminus of the original Fsp27 (Fsp27α). White adipose tissue (WAT) and the liver specific ...[more]

PMID: 25125366

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Project description:The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4?, HNF1?, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)?, and CEBP?. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho-ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p-ERM], phospho-myosin light chain [p-MLC], low-density lipoprotein receptor-related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child-Pugh classification, Model for End-Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4? expression was down-regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4? expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho-associated protein kinase pathways, which have been implicated in the regulation of HNF4?, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4? and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582-594).

Dataset Information

Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis.

Publications

Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis.

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