FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice

Kamagate, Adama; Shen Qu; Perdomo, German; Dongming Su; Dae Hyun Kim; Slusher, Sandra; Meseck, Marcia; Dong, H. Henry; Qu, Shen; Su, Dongming; Kim, Dae Hyun
June 2008
Journal of Clinical Investigation;Jun2008, Vol. 118 Issue 6, p2347
Academic Journal
journal article
Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP regulation by forkhead box O1 (FoxO1), a transcription factor that plays a key role in hepatic insulin signaling. In HepG2 cells, MTP expression was induced by FoxO1 and inhibited by exposure to insulin. This effect correlated with the ability of FoxO1 to bind and stimulate MTP promoter activity. Deletion or mutation of the FoxO1 target site within the MTP promoter disabled FoxO1 binding and resulted in abolition of insulin-dependent regulation of MTP expression. We generated mice that expressed a constitutively active FoxO1 transgene and found that increased FoxO1 activity was associated with enhanced MTP expression, augmented VLDL production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of hepatic FoxO1 was associated with reduced MTP and VLDL production in adult mice. Furthermore, we found that hepatic FoxO1 abundance and MTP production were increased in mice with abnormal triglyceride metabolism. These data suggest that FoxO1 mediates insulin regulation of MTP production and that augmented MTP levels may be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.


Related Articles

  • Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance. Wanzhu Jin; Goldfine, Allison B.; Boes, Tanner; Henry, Robert R.; Ciaraldi, Theodore P.; Eun-Young Kim; Emecan, Merve; Fitzpatrick, Connor; Sen, Anish; Shah, Ankit; Mun, Edward; Vokes, Martha; Schroeder, Joshua; Tatro, Elizabeth; Jimenez-Chillaron, Jose; Patti, Mary-Elizabeth; Jin, Wanzhu; Kim, Eun-Young; Vokes, Vokes // Journal of Clinical Investigation;Mar2011, Vol. 121 Issue 3, p918 

    Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a...

  • Phosphorylation substrates and altered signalling in leukemias caused by BCR/ABL. Groffen, J.; De Jong, R.; Haataja, L.; Kaartinen, V.; Heisterkamp, N. // Leukemia (08876924);Apr1999 Supplement 1, Vol. 13, pS81 

    The article presents information related to a study which demonstrates that tyrosine-phosphorylated proteins which specifically bind to the Crkl SH2 domain in the leukemic tissues of P190 BCR/ABL transgenic mice are identical to Hef1 /Cas-L. According to the study, Hef1 /Cas-L is similar to p130...

  • Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. Banks, Alexander S.; Jianze Li; McKeag, Lisa; Hribal, Marta L.; Kashiwada, Masaki; Accili, Domenico; Rothman, Paul B.; Li, Jianze // Journal of Clinical Investigation;Sep2005, Vol. 115 Issue 9, p2462 

    NIDDM is characterized by progressive insulin resistance and the failure of insulin-producing pancreatic beta cells to compensate for this resistance. Hyperinsulinemia, inflammation, and prolonged activation of the insulin receptor (INSR) have been shown to induce insulin resistance by...

  • Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. Debies, Michael T.; Gestl, Shelley A.; Mathers, Jessica L.; Mikse, Oliver R.; Leonard, Travis L.; Moody, Susan E.; Chodosh, Lewis A.; Cardiff, Robert D.; Gunther, Edward J. // Journal of Clinical Investigation;Jan2008, Vol. 118 Issue 1, p51 

    Breast cancers frequently progress or relapse during targeted therapy, but the molecular mechanisms that enable escape remain poorly understood. We elucidated genetic determinants underlying tumor escape in a transgenic mouse model of Wnt pathway-driven breast cancer, wherein targeted therapy is...

  • Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Yakar, Shoshana; Liu, Jun-Li; Fernandez, Ana M.; Wu, Yiping; Schally, Andrew V.; Frystyk, Jan; Chernausek, Steve D.; Mejia, Wilson; Le Roith, Derek; Yakar, S; Liu, J L; Fernandez, A M; Wu, Y; Schally, A V; Frystyk, J; Chernausek, S D; Mejia, W; Le Roith, D // Diabetes;May2001, Vol. 50 Issue 5, p1110 

    Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (approximately 75%) in...

  • Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice. Buettner, Christoph; Patel, Rima; Muse, Evan D.; Bhanot, Sanjay; Monia, Brett P.; Mckay, Rob; Obici, Silvana; Rossetti, Luciano // Journal of Clinical Investigation;May2005, Vol. 115 Issue 5, p1306 

    Insulin exerts its potent effects on hepatic glucose fluxes via direct and indirect mechanisms. Whereas a liver-specific insulin receptor (IR) knockout (LIRKO) mouse exhibits glucose intolerance as well as insulin resistance, it is unclear whether a more acute decrease in the expression of...

  • Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation. Kasai, Kazuo; Ohara-Imaizumi, Mica; TakahashiA, Noriko; Mizutani, Shin; Zhao, Shengli; Kikuta, Toshiteru; Kasai, Haruo; Nagamatsu, Shinya; Gomi, Hiroshi; Izumi, Tetsuro; Takahashi, Noriko // Journal of Clinical Investigation;Feb2005, Vol. 115 Issue 2, p388 

    The monomeric small GTPase Rab27a is specifically localized on both secretory granules and lysosome-related organelles. Although natural mutations of the Rab27a gene in human Griscelli syndrome and in ashen mice cause partial albinism and immunodeficiency reflecting the dysfunction of...

  • SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. Evel-Kabler, Kevin; Song, Xiao-Tong; Aldrich, Melissa; Huang, Xue F.; Chen, Si-Yi // Journal of Clinical Investigation;Jan2006, Vol. 116 Issue 1, p90 

    DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that...

  • Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. Serezani, Carlos H.; Lewis, Casey; Jancar, Sonia; Peters-Golden, Marc // Journal of Clinical Investigation;Feb2011, Vol. 121 Issue 2, p671 

    Activation of NF-κB and 5-lipoxygenase-mediated (5-LO-mediated) biosynthesis of the lipid mediator leukotriene B4 (LTB4) are pivotal components of host defense and inflammatory responses. However, the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics