Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis - PubMed (original) (raw)
doi: 10.1016/j.cmet.2007.11.013.
Antonio Hernandez-Ono, Christian Rask-Madsen, Joel T Haas, José O Alemán, Ryo Suzuki, Erez F Scapa, Chhavi Agarwal, Martin C Carey, Gregory Stephanopoulos, David E Cohen, George L King, Henry N Ginsberg, C Ronald Kahn
Affiliations
- PMID: 18249172
- PMCID: PMC4251554
- DOI: 10.1016/j.cmet.2007.11.013
Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
Sudha B Biddinger et al. Cell Metab. 2008 Feb.
Abstract
Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.
Figures
Figure 1. FPLC profiles of plasma lipoproteins from Lox and LIRKO mice
Serum was obtained from six month old mice on a normal chow diet, after a 4.5 hour fast, and (A) total cholesterol or (B) triglycerides was measured (n=5-6, p=0.04). Serum was subjected to FPLC analysis, and (C) cholesterol and (D) triglycerides were measured in each of the eluted fractions. Data are presented as the average of 2-4 mice per genotype. Similar results were obtained in two other experiments. (E) Apolipoprotein levels were examined by immunoblotting whole serum (left) or serum subjected to fractionation by FPLC. FPLC samples were prepared by pooling equal volumes of each fraction from three mice. In this and all other figures, error bars represent the SEM.
Figure 2. Insulin resistance alters gene expression
(A) Expression of the PGC and SREBP expression was measured in the livers of two-month old, non-fasted mice on a chow diet by real time PCR analysis or immunoblotting of liver extracts (PGC-1) or nuclear extracts (SREBP-1). SREBP-1 protein was also measured in two-month old mice after fasting and re-feeding (n=4-8, *p<0.05,). (B) Real time PCR analysis of cDNA prepared from the livers of two to four month old non-fasted chow fed mice. See text for gene names. (C) Two-month old Lox and LIRKO mice were gavaged with 40 mg/kg LXR agonist (T090137) or vehicle every 24 hours for two doses, and sacrificed four hours after the second dose, in the non-fasted state. Real time PCR was performed on cDNA prepared from these livers (n=5-8, *p<0.05, **p<0.005). (D) Hepatocytes were isolated from two to three month old Lox and LIRKO mice, and cultured overnight in the presence of 100 nM insulin, and either 5 μM LXR agonist or vehicle. RNA was extracted and subjected to real time PCR analysis. (n=4-6, *p<0.05)
Figure 3. VLDL metabolism
A-C) Two- to three- month old chow-fed Lox and LIRKO mice were injected with Triton WR1339 after a six hour fast. Serum triglycerides were measured at 0, 90 and 180 minutes (n=5-7, p ≤ 0.01 at each time point). After 180 minutes, serum was collected and equal volumes were pooled, and subjected to ultracentrifugation to obtain the VLDL fraction. VLDL triglycerides (A) and cholesterol (B) were measured. (D, E) apoB secretion and VLDL clearance were measured in four-month old mice after ten weeks on the Western diet. (D) The rate of apoB synthesis was measured as the amount of radiolabeled apoB100 and apoB48 present in the serum one hour after the injection of Triton WR1339 and [35S]methionine, normalized to the amount present in the Lox control (n=4-5, *p<0.01) (E) Fractional clearance of LDL apoB was determined by measuring plasma radioactivity over 24 hrs after injection of 125I –labeled mouse LDL. Results are expressed as the percentage of LDL radioactivity remaining in plasma at each time point (n=3). Inset shows LDL receptor immunoblot of liver extracts prepared from these mice.
Figure 4. Dyslipidemia and Atherosclerosis on the Atherogenic Diet
A-D) Serum was obtained from four month old mice fed the atherogenic diet for two months, after a six hour fast. Total cholesterol (A) and triglycerides (B) were measured in the serum. Equal amounts of serum were pooled from two mice of each genotype, and subjected to FPLC fractionation. Cholesterol (C) and triglycerides (D) were measured in each fraction. Data are presented as an average of three samples per genotype. E-F) Lox and LIRKO mice were placed on an atherogenic diet at two months of age, and sacrificed three to four months later, at which time the aorta was examined for the presence of atherosclerosis (E) Quantitation of the plaque area in Lox and LIRKO mice (*p=0.01, using a Mann-Whitney U-test). (F) Gross dissected anatomy in situ (left); sections through aortic sinus and the aortic valve stained with hematoxylin and eosin (middle); and entire aorta with adventitial fat carefully removed, flat mounted “en face” and stained for fat with Sudan IV (right).
Comment in
- Selective versus total insulin resistance: a pathogenic paradox.
Brown MS, Goldstein JL. Brown MS, et al. Cell Metab. 2008 Feb;7(2):95-6. doi: 10.1016/j.cmet.2007.12.009. Cell Metab. 2008. PMID: 18249166 Review.
Similar articles
- Sterol carrier protein-2 deficiency attenuates diet-induced dyslipidemia and atherosclerosis in mice.
He H, Wang J, Yannie PJ, Kakiyama G, Korzun WJ, Ghosh S. He H, et al. J Biol Chem. 2018 Jun 15;293(24):9223-9231. doi: 10.1074/jbc.RA118.002290. Epub 2018 Apr 26. J Biol Chem. 2018. PMID: 29700117 Free PMC article. - Pathophysiology of Diabetic Dyslipidemia.
Hirano T. Hirano T. J Atheroscler Thromb. 2018 Sep 1;25(9):771-782. doi: 10.5551/jat.RV17023. Epub 2018 Jul 12. J Atheroscler Thromb. 2018. PMID: 29998913 Free PMC article. Review. - Lipid and lipoprotein dysregulation in insulin resistant states.
Avramoglu RK, Basciano H, Adeli K. Avramoglu RK, et al. Clin Chim Acta. 2006 Jun;368(1-2):1-19. doi: 10.1016/j.cca.2005.12.026. Epub 2006 Feb 9. Clin Chim Acta. 2006. PMID: 16480697 Review. - Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.
Han S, Liang CP, Westerterp M, Senokuchi T, Welch CL, Wang Q, Matsumoto M, Accili D, Tall AR. Han S, et al. J Clin Invest. 2009 Apr;119(4):1029-41. doi: 10.1172/JCI36523. Epub 2009 Mar 9. J Clin Invest. 2009. PMID: 19273907 Free PMC article. - Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance.
Mulvihill EE, Assini JM, Lee JK, Allister EM, Sutherland BG, Koppes JB, Sawyez CG, Edwards JY, Telford DE, Charbonneau A, St-Pierre P, Marette A, Huff MW. Mulvihill EE, et al. Diabetes. 2011 May;60(5):1446-57. doi: 10.2337/db10-0589. Epub 2011 Apr 6. Diabetes. 2011. PMID: 21471511 Free PMC article.
Cited by
- Metabolic Syndrome and Biotherapeutic Activity of Dairy (Cow and Buffalo) Milk Proteins and Peptides: Fast Food-Induced Obesity Perspective-A Narrative Review.
Abdisa KB, Szerdahelyi E, Molnár MA, Friedrich L, Lakner Z, Koris A, Toth A, Nath A. Abdisa KB, et al. Biomolecules. 2024 Apr 14;14(4):478. doi: 10.3390/biom14040478. Biomolecules. 2024. PMID: 38672494 Free PMC article. Review. - Protein neddylation and its role in health and diseases.
Zhang S, Yu Q, Li Z, Zhao Y, Sun Y. Zhang S, et al. Signal Transduct Target Ther. 2024 Apr 5;9(1):85. doi: 10.1038/s41392-024-01800-9. Signal Transduct Target Ther. 2024. PMID: 38575611 Free PMC article. Review. - Recent Advances in Hepatic Metabolic Regulation by the Nuclear Factor Rev-erbɑ.
Zhang Q, Chen Y, Li J, Xia H, Tong Y, Liu Y. Zhang Q, et al. Curr Drug Metab. 2024;25(1):2-12. doi: 10.2174/0113892002290055240212074758. Curr Drug Metab. 2024. PMID: 38409696 Review. - Predictors of controlled attenuation parameter in metabolic dysfunction.
Bianco C, Pelusi S, Margarita S, Tavaglione F, Jamialahmadi O, Malvestiti F, Periti G, Rondena J, Tomasi M, Carpani R, Ronzoni L, Vidali M, Ceriotti F, Fraquelli M, Vespasiani-Gentilucci U, Romeo S, Prati D, Valenti L. Bianco C, et al. United European Gastroenterol J. 2024 Apr;12(3):364-373. doi: 10.1002/ueg2.12513. Epub 2023 Dec 23. United European Gastroenterol J. 2024. PMID: 38141028 Free PMC article. - To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism.
Ianiro G, Niro A, Rosa L, Valenti P, Musci G, Cutone A. Ianiro G, et al. Int J Mol Sci. 2023 Nov 3;24(21):15925. doi: 10.3390/ijms242115925. Int J Mol Sci. 2023. PMID: 37958908 Free PMC article. Review.
References
- Argmann CA, Houten SM, Champy MF, Auwerx J. Lipid and Bile Acid Analysis. John Wiley & Sons, Inc; 2006. Current Protocols in Molecular Biology; pp. 29B.2.1–29B.2.24. - PubMed
- Babaev VR, Patel MB, Semenkovich CF, Fazio S, Linton MF. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice. J Biol Chem. 2000;275:26293–26299. - PubMed
- Bartels ED, Lauritsen M, Nielsen LB. Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes. 2002;51:1233–1239. - PubMed
- Baumgartl J, Baudler S, Scherner M, Babaev V, Makowski L, Suttles J, McDuffie M, Tobe K, Kadowaki T, Fazio S, Kahn CR, Hotamisligil GS, Krone W, Linton M, Bruning JC. Myeloid lineage cell-restricted insulin resistance protects apolipoprotein E-deficient mice against atherosclerosis. Cell Metab. 2006;3:247–256. - PMC - PubMed
- Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn CR. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Diabetes. 2005;54:1314–1323. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- HL55368/HL/NHLBI NIH HHS/United States
- DK45935/DK/NIDDK NIH HHS/United States
- R01 DK056626/DK/NIDDK NIH HHS/United States
- DK59637-01/DK/NIDDK NIH HHS/United States
- DK053105/DK/NIDDK NIH HHS/United States
- R01 HL073030/HL/NHLBI NIH HHS/United States
- R37 DK048873/DK/NIDDK NIH HHS/United States
- R37 DK031036/DK/NIDDK NIH HHS/United States
- R01 DK075850/DK/NIDDK NIH HHS/United States
- U24 DK059637/DK/NIDDK NIH HHS/United States
- R01 DK073687/DK/NIDDK NIH HHS/United States
- DK75850/DK/NIDDK NIH HHS/United States
- P30 DK36836/DK/NIDDK NIH HHS/United States
- P30 DK036836/DK/NIDDK NIH HHS/United States
- K08DK073358/DK/NIDDK NIH HHS/United States
- DK31036/DK/NIDDK NIH HHS/United States
- R01 DK053105/DK/NIDDK NIH HHS/United States
- R01 DK048873/DK/NIDDK NIH HHS/United States
- K12 DK063696/DK/NIDDK NIH HHS/United States
- DK073687/DK/NIDDK NIH HHS/United States
- HL73030/HL/NHLBI NIH HHS/United States
- DK036588/DK/NIDDK NIH HHS/United States
- R01 DK045935/DK/NIDDK NIH HHS/United States
- R01 DK031036/DK/NIDDK NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases