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Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression.
J Biol Chem 2003; 278(44):43095-101JB

Abstract

Like hyperglycemia, postprandial (diet-induced) hypertriglyceridemia is thought to play crucial roles in the pathogenesis of insulin resistant/metabolic syndrome. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor to induce postprandial hypertriglyceridemia. We found that insulin-resistant rats fed a diet high in fructose showed an increased proteintyrosine phosphatase 1B (PTP1B) content with strong expression of SREBP-1 mRNA in the liver. To clarify the association of PTP1B with SREBP-1 gene expression, we overexpressed PTP1B in rat hepatocytes, which led to increased mRNA content and promoter activity of SREBP-1a and -1c, resulting in the increased mRNA expression of fatty-acid synthase, one of the SREBP-1-responsive lipogenic genes. Because PTP1B overexpression increased phosphatase 2A (PP2A) activity, we inhibited PP2A activity by expression of its selective inhibitor, SV40 small T antigen and found that this normalized the PTP1B-enhanced SREBP-1a and -1c mRNA expressions through activation of the Sp1 site. These results indicate that PTP1B may regulate gene expression of SREBP-1 via enhancement of PP2A activity, thus mediating hepatic lipogenesis and postprandial hypertriglyceridemia. We demonstrate here a unique serial activation of the PTP1B-PP2A axis as a novel mechanism for the regulation of gene expression in the biosynthesis of triglyceride.

Authors+Show Affiliations

Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

12941932

Citation

Shimizu, Shinya, et al. "Protein-tyrosine Phosphatase 1B as New Activator for Hepatic Lipogenesis Via Sterol Regulatory Element-binding Protein-1 Gene Expression." The Journal of Biological Chemistry, vol. 278, no. 44, 2003, pp. 43095-101.
Shimizu S, Ugi S, Maegawa H, et al. Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression. J Biol Chem. 2003;278(44):43095-101.
Shimizu, S., Ugi, S., Maegawa, H., Egawa, K., Nishio, Y., Yoshizaki, T., ... Kashiwagi, A. (2003). Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression. The Journal of Biological Chemistry, 278(44), pp. 43095-101.
Shimizu S, et al. Protein-tyrosine Phosphatase 1B as New Activator for Hepatic Lipogenesis Via Sterol Regulatory Element-binding Protein-1 Gene Expression. J Biol Chem. 2003 Oct 31;278(44):43095-101. PubMed PMID: 12941932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression. AU - Shimizu,Shinya, AU - Ugi,Satoshi, AU - Maegawa,Hiroshi, AU - Egawa,Katsuya, AU - Nishio,Yoshihiko, AU - Yoshizaki,Takeshi, AU - Shi,Kun, AU - Nagai,Yoshio, AU - Morino,Katsutaro, AU - Nemoto,Ken-ichi, AU - Nakamura,Takaaki, AU - Bryer-Ash,Michael, AU - Kashiwagi,Atsunori, Y1 - 2003/08/26/ PY - 2003/8/28/pubmed PY - 2003/12/25/medline PY - 2003/8/28/entrez SP - 43095 EP - 101 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 44 N2 - Like hyperglycemia, postprandial (diet-induced) hypertriglyceridemia is thought to play crucial roles in the pathogenesis of insulin resistant/metabolic syndrome. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor to induce postprandial hypertriglyceridemia. We found that insulin-resistant rats fed a diet high in fructose showed an increased proteintyrosine phosphatase 1B (PTP1B) content with strong expression of SREBP-1 mRNA in the liver. To clarify the association of PTP1B with SREBP-1 gene expression, we overexpressed PTP1B in rat hepatocytes, which led to increased mRNA content and promoter activity of SREBP-1a and -1c, resulting in the increased mRNA expression of fatty-acid synthase, one of the SREBP-1-responsive lipogenic genes. Because PTP1B overexpression increased phosphatase 2A (PP2A) activity, we inhibited PP2A activity by expression of its selective inhibitor, SV40 small T antigen and found that this normalized the PTP1B-enhanced SREBP-1a and -1c mRNA expressions through activation of the Sp1 site. These results indicate that PTP1B may regulate gene expression of SREBP-1 via enhancement of PP2A activity, thus mediating hepatic lipogenesis and postprandial hypertriglyceridemia. We demonstrate here a unique serial activation of the PTP1B-PP2A axis as a novel mechanism for the regulation of gene expression in the biosynthesis of triglyceride. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12941932/Protein_tyrosine_phosphatase_1B_as_new_activator_for_hepatic_lipogenesis_via_sterol_regulatory_element_binding_protein_1_gene_expression_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12941932 DB - PRIME DP - Unbound Medicine ER -