Hepatic Insulin Signaling Is Required for Obesity-Dependent Expression of SREBP-1c mRNA but Not for Feeding-Dependent Expression

被引：164

作者：

Haas, Joel T. ^{[2
]}

Miao, Ji ^{[1
]}

Chanda, Dipanjan ^{[1
]}

Wang, Yanning ^{[1
]}

Zhao, Enpeng ^{[1
]}

Haas, Mary E. ^{[1
]}

Hirschey, Matthew ^{[5
]}

Vaitheesvaran, B. ^{[6
]}

Farese, Robert V., Jr. ^{[2
,3
,4
]}

Kurland, Irwin J. ^{[6
]}

Graham, Mark ^{[7
]}

Crooke, Rosanne ^{[7
]}

Foufelle, Fabienne ^{[8
,9
]}

Biddinger, Sudha B. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Div Endocrinol, Childrens Hosp Boston, Boston, MA 02115 USA

[2] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94158 USA

[5] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27710 USA

[6] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA

[7] ISIS Pharmaceut, Carlsbad, CA 92010 USA

[8] INSERM, UMR S 872, Ctr Rech Cordeliers, Paris, France

[9] Univ Paris 06, Paris, France

来源：

CELL METABOLISM | 2012年 / 15卷 / 06期

关键词：

ELEMENT-BINDING PROTEIN-1C; FATTY LIVER-DISEASE; METABOLIC SYNDROME; ACID SYNTHESIS; X-RECEPTOR; RESISTANCE; ACTIVATION; MICE; FRUCTOSE; LIPOGENESIS;

D O I：

10.1016/j.cmet.2012.05.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.

引用

页码：873 / 884

页数：12

共 47 条

[1] Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats [J].

Anai, M ;

Funaki, M ;

Ogihara, T ;

Kanda, A ;

Onishi, Y ;

Sakoda, H ;

Inukai, K ;

Nawano, M ;

Fukushima, Y ;

Yazaki, Y ;

Kikuchi, M ;

Oka, Y ;

Asano, T .

DIABETES, 1999, 48 (01) :158-169

[2] From mice to men: Insights into the insulin resistance syndromes [J].

Biddinger, SB ;

Kahn, CR .

ANNUAL REVIEW OF PHYSIOLOGY, 2006, 68 :123-158

[3] Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome [J].

Biddinger, SB ;

Almind, K ;

Miyazaki, M ;

Kokkotou, E ;

Ntambi, JM ;

Kahn, CR .

DIABETES, 2005, 54 (05) :1314-1323

[4] Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis [J].

Biddinger, Sudha B. ;

Hernandez-Ono, Antonio ;

Rask-Madsen, Christian ;

Haas, Joel T. ;

Aleman, Jose O. ;

Suzuki, Ryo ;

Scapa, Erez F. ;

Agarwal, Chhavi ;

Carey, Martin C. ;

Stephanopoulos, Gregory ;

Cohen, David E. ;

King, George L. ;

Ginsberg, Henry N. ;

Kahn, C. Ronald .

CELL METABOLISM, 2008, 7 (02) :125-134

[5] Selective versus total insulin resistance: A pathogenic paradox [J].

Brown, Michael S. ;

Goldstein, Joseph L. .

CELL METABOLISM, 2008, 7 (02) :95-96

[6] Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver [J].

Chen, GX ;

Liang, GS ;

Ou, JF ;

Goldstein, JL ;

Brown, MS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (31) :11245-11250

[7] Nonalcoholic fatty liver disease in type 2 diabetes mellitus [J].

Cusi, Kenneth .

CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY, 2009, 16 (02) :141-149

[8] STRUCTURAL AND FUNCTIONAL HOMOLOGIES IN THE RECEPTORS FOR INSULIN AND THE INSULIN-LIKE GROWTH-FACTORS [J].

CZECH, MP .

CELL, 1982, 31 (01) :8-10

[9] ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver [J].

Denechaud, Pierre-Damien ;

Bossard, Pascale ;

Lobaccaro, Jean-Marc A. ;

Millatt, Lesley ;

Staels, Bart ;

Girard, Jean ;

Postic, Catherine .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (03) :956-964

[10] Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression [J].

Dentin, R ;

Pégorier, JP ;

Benhamed, F ;

Foufelle, F ;

Ferré, P ;

Fauveau, V ;

Magnuson, MA ;

Girard, J ;

Postic, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (19) :20314-20326

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