Dataset Information

Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2? and regulation of bile acid homeostasis.

ABSTRACT: Cholesterol synthesis is a highly oxygen-dependent process. Paradoxically, hypoxia is correlated with an increase in cellular and systemic cholesterol levels and risk of cardiovascular diseases. The mechanism for the increase in cholesterol during hypoxia is unclear. Hypoxia signaling is mediated through hypoxia-inducible factor 1? (HIF-1?) and HIF-2?. The present study demonstrates that activation of HIF signaling in the liver increases hepatic and systemic cholesterol levels due to a decrease in the expression of cholesterol hydroxylase CYP7A1 and other enzymes involved in bile acid synthesis. Specifically, activation of hepatic HIF-2? (but not HIF-1?) led to hypercholesterolemia. HIF-2? repressed the circadian expression of Rev-erb?, resulting in increased expression of E4BP4, a negative regulator of Cyp7a1. To understand if HIF-mediated decrease in bile acid synthesis is a physiologically relevant pathway by which hypoxia maintains or increases systemic cholesterol levels, two hypoxic mouse models were assessed, an acute lung injury model and mice exposed to 10% O2 for 3 weeks. In both models, cholesterol levels increased with a concomitant decrease in expression of genes involved in bile acid synthesis. The present study demonstrates that hypoxic activation of hepatic HIF-2? leads to an adaptive increase in cholesterol levels through inhibition of bile acid synthesis.

SUBMITTER: Ramakrishnan SK

PROVIDER: S-EPMC3993569 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2α and regulation of bile acid homeostasis.

Ramakrishnan Sadeesh K SK Taylor Matthew M Qu Aijuan A Ahn Sung-Hoon SH Suresh Madathilparambil V MV Raghavendran Krishnan K Gonzalez Frank J FJ Shah Yatrik M YM

Molecular and cellular biology 20140113 7

Cholesterol synthesis is a highly oxygen-dependent process. Paradoxically, hypoxia is correlated with an increase in cellular and systemic cholesterol levels and risk of cardiovascular diseases. The mechanism for the increase in cholesterol during hypoxia is unclear. Hypoxia signaling is mediated through hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. The present study demonstrates that activation of HIF signaling in the liver increases hepatic and systemic cholesterol levels due to a decrease ...[more]

PMID: 24421394

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Project description:The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in alpha-cells or an insulin promoter in beta-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.

Dataset Information

Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2? and regulation of bile acid homeostasis.

Publications

Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2α and regulation of bile acid homeostasis.

Similar Datasets

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