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Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis.

ABSTRACT: Nucleotide hydrolysis is essential for many aspects of cellular function. In the case of 3',5'-bisphosphorylated nucleotides, mammals possess two related 3'-nucleotidases, Golgi-resident 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase (gPAPP) and Bisphosphate 3'-nucleotidase 1 (Bpnt1). gPAPP and Bpnt1 localize to distinct subcellular compartments and are members of a conserved family of metal-dependent lithium-sensitive enzymes. Although recent studies have demonstrated the importance of gPAPP for proper skeletal development in mice and humans, the role of Bpnt1 in mammals remains largely unknown. Here we report that mice deficient for Bpnt1 do not exhibit skeletal defects but instead develop severe liver pathologies, including hypoproteinemia, hepatocellular damage, and in severe cases, frank whole-body edema and death. Accompanying these phenotypes, we observed tissue-specific elevations of the substrate PAP, up to 50-fold in liver, repressed translation, and aberrant nucleolar architecture. Remarkably, the phenotypes of the Bpnt1 knockout are rescued by generating a double mutant mouse deficient for both PAP synthesis and hydrolysis, consistent with a mechanism in which PAP accumulation is toxic to tissue function independent of sulfation. Overall, our study defines a role for Bpnt1 in mammalian physiology and provides mechanistic insights into the importance of sulfur assimilation and cytoplasmic PAP hydrolysis to normal liver function.

SUBMITTER: Hudson BH

PROVIDER: S-EPMC3612647 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis.

Hudson Benjamin H BH Frederick Joshua P JP Drake Li Yin LY Megosh Louis C LC Irving Ryan P RP York John D JD

Proceedings of the National Academy of Sciences of the United States of America 20130311 13

Nucleotide hydrolysis is essential for many aspects of cellular function. In the case of 3',5'-bisphosphorylated nucleotides, mammals possess two related 3'-nucleotidases, Golgi-resident 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase (gPAPP) and Bisphosphate 3'-nucleotidase 1 (Bpnt1). gPAPP and Bpnt1 localize to distinct subcellular compartments and are members of a conserved family of metal-dependent lithium-sensitive enzymes. Although recent studies have demonstrated the importance of gPAP ...[more]

PMID: 23479625

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Project description:BackgroundPPARs (?,?,?) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Methods/principal findingsUsing PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL?LDL, IDL) to activate PPAR? preferentially over PPAR? or PPAR?, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPAR? in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPAR? target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPAR? activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPAR? activation and ADRP gene regulation in vitro.ConclusionsThese data define a novel pathway involving HL hydrolysis of VLDL that activates PPAR? through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.

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Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis.

Publications

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis.

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