Liver Receptor Homolog 1 Controls the Expression of Carboxyl Ester Lipase

Fayard, Elisabeth; Schoonjans, Kristina; Annicotte, Jean-Sébastien; Auwerx, Johan

doi:10.1074/jbc.m302370200

Cited by 53 publications

(38 citation statements)

References 48 publications

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“…A model emerged whereby FTF would act as a "competence" factor driving the BA pathway, subject to negative feedback regulation by interaction of FTF with orphan receptor SHP, activated by the BA receptor FXR and by FTF itself (15,16,18,19). Additional reports associated further FTF action with membrane transporters of the enterohepatic BA recycling system (20,21) and with pancreatic cholesterol esterase (22), all of which pointing to an important systemic role for FTF in adult cholesterol/BA homeostasis.…”

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confidence: 99%

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Paré

Malenfant

Courtemanche

et al. 2004

Journal of Biological Chemistry

145

134

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Development of the mammalian embryo relies upon nutritive functions fulfilled by the visceral endoderm and then by the liver (1). A part of these functions is accomplished by nutrient carrier proteins of the albumin gene family, a multigene locus expressed by the liver and subject to precise developmental controls. One albumin-related gene, the ␣ 1 -fetoprotein (AFP) 1 gene, is activated at the onset of liver differentiation and operates tightly coupled with liver growth (2, 3). In 1988, our group circumscribed a proximal AFP promoter element essential to AFP gene activity in hepatocytes, and distinct from promoter components regulating the other albumin loci (4). The AFP-specific activator was then identified as orphan receptor fetoprotein transcription factor (5-7), so named for its first identified target locus (genome data base nomenclature, 2 NR5A2 in the nuclear receptor nomenclature, Ref. 9); also referred to as LRH1 or CPF). FTF belonged to a primitive class of nuclear receptors and emerged as a critical lead to connect AFP gene activation with early embryonic growth and differentiation processes.Subsequent studies indicated that developmental FTF functions even preceded its activation of the AFP locus in hepatocytes. In situ hybridization analysis in the mouse at embryonic day 8 -9 showed abundant FTF transcripts in the foregut endoderm, before liver morphogenesis (10). Characterization of the FTF gene promoter also revealed a cluster of regulatory motifs conserved in distant species and potential targets of cell lineage specification factors (11). Among these were three proximal binding sites for GATA factors, known to be essential for visceral endoderm function (12, 13). Furthermore, three HNF genes important to liver differentiation, HNF1␣, HNF4␣, and HNF3␤, were found to each contain double FTF-binding sites in their proximal promoter and to be activated by FTF in transfection assays (11). Thus, a pivotal role was suggested for FTF in a transcriptional cascade using determination factors to activate FTF in prehepatic endodermal cells, and then using FTF to drive AFP and other effectors of the hepatic program.

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confidence: 99%

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Paré

Malenfant

Courtemanche

et al. 2004

Journal of Biological Chemistry

145

134

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“…LRH-1 is also expressed in both the acinar and ductal cells of the exocrine pancreas (Rausa et al 1999). While LRH-1 regulates expression of carboxyl ester lipase in acinar cells (Fayard et al 2003), little else is known about its function in this tissue. Here, we investigated the function of LRH-1 in exocrine pancreas.…”

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confidence: 99%

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Holmstrom¹,

Deering²,

Swift³

et al. 2011

Genes Dev.

112

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We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulating exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid.

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“…3). In adults, this protein is expressed primarily in liver, intestine, and pancreas, where it regulates expression of proteins maintaining cholesterol homeostasis (3,4). LRH-1 is also expressed in the ovary and breast adipose tissue where it controls biosynthesis of steroids (5,6).…”

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confidence: 99%

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

Benod

Vinogradova

Jouravel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

125

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An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.protein target | gene regulation W ith mortality rate nearing its incidence, pancreatic ductal adenocarcinoma (PDAC) presents a challenge for modern oncology. Current chemotherapy drugs approved for pancreatic cancer are not organ specific and are modestly effective. Thus, there is a need for improved therapeutic options and effective pancreatic cancer drugs. Recent studies reveal that signaling pathways are similar in pancreatic development and malignant growth in the adult pancreas (1, 2). One of the common driving factors in pancreatic embryo-and oncogenesis is the nuclear receptor liver receptor homologue 1 (LRH-1,

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Liver Receptor Homolog 1 Controls the Expression of Carboxyl Ester Lipase

Cited by 53 publications

References 48 publications

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

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