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SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease.
Int J Mol Med. 2008 Apr; 21(4):507-11.IJ

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease whose prevalence has increased markedly. We reported previously that fatty acid synthesis was enhanced in NAFLD with the accumulation of fatty acids. To clarify the disorder, we evaluated the expression of genes regulating fatty acid synthesis by real-time PCR using samples from NAFLD (n=22) and normal liver (control; n=10). A major regulator of fatty acids synthesis is sterol regulatory element-binding protein-1c (SREBP-1c). Its expression was significantly higher in NAFLD, nearly 5-fold greater than the controls. SREBP-1c is positively regulated by insulin signaling pathways, including insulin receptor substrate (IRS)-1 and -2. In NAFLD, IRS-1 expression was enhanced and correlated positively with SREBP-1c expression. In contrast, IRS-2 expression decreased by 50% and was not correlated with SREBP-1c. Forkhead box protein A2 (Foxa2) is a positive regulator of fatty acid oxidation and is itself negatively regulated by IRSs. Foxa2 expression increased in NAFLD and showed a negative correlation with IRS-2, but not with IRS-1, expression. It is known that SREBP-1c is negatively regulated by AMP-activated protein kinase (AMPK) but expression levels of AMPK in NAFLD were almost equal to those of the controls. These data indicate that, in NAFLD, insulin signaling via IRS-1 causes the up-regulation of SREBP1-c, leading to the increased synthesis of fatty acids by the hepatocytes; negative feedback regulation via AMPK does not occur and the activation of Foxa2, following a decrease of IRS-2, up-regulates fatty acid oxidation.

Authors+Show Affiliations

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 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 available

Pub Type(s)

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

Language

eng

PubMed ID

18360697

Citation

Kohjima, Motoyuki, et al. "SREBP-1c, Regulated By the Insulin and AMPK Signaling Pathways, Plays a Role in Nonalcoholic Fatty Liver Disease." International Journal of Molecular Medicine, vol. 21, no. 4, 2008, pp. 507-11.
Kohjima M, Higuchi N, Kato M, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008;21(4):507-11.
Kohjima, M., Higuchi, N., Kato, M., Kotoh, K., Yoshimoto, T., Fujino, T., Yada, M., Yada, R., Harada, N., Enjoji, M., Takayanagi, R., & Nakamuta, M. (2008). SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. International Journal of Molecular Medicine, 21(4), 507-11.
Kohjima M, et al. SREBP-1c, Regulated By the Insulin and AMPK Signaling Pathways, Plays a Role in Nonalcoholic Fatty Liver Disease. Int J Mol Med. 2008;21(4):507-11. PubMed PMID: 18360697.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. AU - Kohjima,Motoyuki, AU - Higuchi,Nobito, AU - Kato,Masaki, AU - Kotoh,Kazuhiro, AU - Yoshimoto,Tsuyoshi, AU - Fujino,Tatsuya, AU - Yada,Masayoshi, AU - Yada,Ryoko, AU - Harada,Naohiko, AU - Enjoji,Munechika, AU - Takayanagi,Ryoichi, AU - Nakamuta,Makoto, PY - 2008/3/25/pubmed PY - 2008/6/6/medline PY - 2008/3/25/entrez SP - 507 EP - 11 JF - International journal of molecular medicine JO - Int J Mol Med VL - 21 IS - 4 N2 - Nonalcoholic fatty liver disease (NAFLD) is a common liver disease whose prevalence has increased markedly. We reported previously that fatty acid synthesis was enhanced in NAFLD with the accumulation of fatty acids. To clarify the disorder, we evaluated the expression of genes regulating fatty acid synthesis by real-time PCR using samples from NAFLD (n=22) and normal liver (control; n=10). A major regulator of fatty acids synthesis is sterol regulatory element-binding protein-1c (SREBP-1c). Its expression was significantly higher in NAFLD, nearly 5-fold greater than the controls. SREBP-1c is positively regulated by insulin signaling pathways, including insulin receptor substrate (IRS)-1 and -2. In NAFLD, IRS-1 expression was enhanced and correlated positively with SREBP-1c expression. In contrast, IRS-2 expression decreased by 50% and was not correlated with SREBP-1c. Forkhead box protein A2 (Foxa2) is a positive regulator of fatty acid oxidation and is itself negatively regulated by IRSs. Foxa2 expression increased in NAFLD and showed a negative correlation with IRS-2, but not with IRS-1, expression. It is known that SREBP-1c is negatively regulated by AMP-activated protein kinase (AMPK) but expression levels of AMPK in NAFLD were almost equal to those of the controls. These data indicate that, in NAFLD, insulin signaling via IRS-1 causes the up-regulation of SREBP1-c, leading to the increased synthesis of fatty acids by the hepatocytes; negative feedback regulation via AMPK does not occur and the activation of Foxa2, following a decrease of IRS-2, up-regulates fatty acid oxidation. SN - 1107-3756 UR - https://www.unboundmedicine.com/medline/citation/18360697/SREBP_1c_regulated_by_the_insulin_and_AMPK_signaling_pathways_plays_a_role_in_nonalcoholic_fatty_liver_disease_ L2 - http://www.spandidos-publications.com/ijmm/21/4/507 DB - PRIME DP - Unbound Medicine ER -