Catalytically Inactive Lipoprotein Lipase Overexpression Increases Insulin Sensitivity in Mice

Abstract

Abnormalities in lipoprotein lipase (LPL) function contribute to the development of hypertriglyceridemia, one of the characteristic disorders observed in the metabolic syndrome. In addition to the hydrolyzing activity of triglycerides, LPL modulates various cellular functions via its binding ability to the cell surface. Here we show the effects of catalytically inactive LPL overexpression on high-fat diet (HFD)-induced decreased systemic insulin sensitivity in mice. The binding capacity of catalytically inactive G188E-LPL to C₂C₁₂ skeletal muscle cells was not significantly different from that of wild type LPL. Insulin-stimulated IRS-1 phosphorylation and glucose uptake were increased by addition of wild type or mutant LPL in C₂C₁₂ cells. After 10 weeks' of HFD feeding, mice had significantly higher blood glucose levels than chow-fed mice in insulin tolerance tests. The blood glucose levels after insulin injection was significantly decreased in mutated LPL-overexpressing mice (G188E mice), as well as in wild type LPL-overexpressing mice (WT mice). Overexpression of catalytically inactive LPL, as well as wild type LPL, improved impaired insulin sensitivity in mice. These results show that decreased expression of LPL possibly causes the insulin resistance, in addition to hypertriglyceridemia, in metabolic syndrome.

Key words

High-fat diet - metabolic syndrome - insulin resistance - cell implantation - skeletal muscle

References

• 1 Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults . Executive summery of the Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults.  JAMA. 2001;  285 2486-2497
• 2 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications.  Diabet Med. 1998;  15 539-553
• 3 Kuriyama H, Yamashita S, Shimomura I, Funahashi T, Ishigami M, Aragane K, Miyaoka K, Nakamura T, Takemura K, Man Z, Toide K, Nakayama N, Fukuda Y, Lin MC, Wetterau JR, Matsuzawa Y. Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation.  Hepatology. 1998;  7 557-562
• 4 Kobayashi J, Kusunoki M, Murase Y, Kawashiri M, Higashikata T, Miwa K, Katsuda S, Takata M, Asano A, Nohara A, Inazu A, Mabuchi H. Relationship of lipoprotein lipase and hepatic triacylglycerol lipase activity to serum adiponectin levels in Japanese hyperlipidemic men.  Horm Metab Res. 2005;  37 505-509
• 5 Olivecrona G, Olivecrona T. Triglyceride lipases and atherosclerosis.  Curr Opin Lipidol. 1995;  6 291-305
• 6 Ong JM, Kirchgessner TG, Schotz MC, Kern PA. Insulin increases the synthetic rate and messenger RNA levels of lipoprotein lipase in isolated rat adipocytes.  J Biol Chem. 1988;  263 12933-12938
• 7 Semenkovich CF, Wims M, Noe L, Etinne J, Chan L. Insulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels.  J Biol Chem. 1989;  264 9030-9038
• 8 Maheux P, Azhar S, Kern PA, Chen YD, Reuven GM. Relationship between insulin-mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase.  Diabetologia. 1997;  40 850-858
• 9 Beisiegel U, Weber W, Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor related proteins.  Proc Natl Acad Sci USA. 1991;  88 8342-8346
• 10 Rumsey SC, Obunike JC, Arad Y, Deckelbaum RJ, Goldberg IJ. Lipoprotein lipase-mediated uptake and degradation of low density lipoproteins by fibroblast and macrophages.  J Clin Invest. 1992;  90 1504-1512
• 11 Kobayashi J, Tashiro J, Bujo H, Morisaki N, Saito Y. Effect of lipoprotein lipase on binding of chylomicrons to LDL receptor-deficient Chinese hamster ovary cells.  Ann Clin Biochem. 2001;  38 124-128
• 12 Merkel M, Kako Y, Radner H, Cho IS, Ramasamy R, Brunzell JD, Goldberg IJ, Breslow JL. Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: Direct evidence that lipoprotein lipase bridging occurs in vivo.  Proc Natl Acad Sci USA. 1998;  95 13841-13846
• 13 Shibasaki M, Takahashi K, Itou T, Miyazawa S, Ito M, Kobayashi J, Bujo H, Saito Y. Alterations of insulin sensitivity by the implantation of 3T3-L1 cells in nude mice.  A role for TNF-α? Diabetologia. 2002;  45 518-526
• 14 Kitagawa Y, Bujo H, Takahashi K, Shibasaki M, Ishikawa K, Yagui K, Hashimoto N, Noda K, Nakamura T, Yano S, Saito Y. Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin.  Diabetologia. 2004;  47 1847-1853
• 15 Emi M, Wilson DE, Iverius PH, Wu L, Hata A, Hegele R, Williams RR, Lalouel JM. Missense mutation (Gly → Glu188) of human lipoprotein lipase imparting functional deficiency.  J Biol Chem. 1990;  265 5910-5916
• 16 Kobayashi J, Hashimoto H, Fukamachi I. et al . Lipoprotein lipase mass and activity in severe hypertriglyceridemia.  Clin Chim Acta. 1993;  216 113-123
• 17 Zhu Y, Bujo H, Takahashi K, Taira K, Kobayashi J, Koshikawa H, Sasaki Y, Kanoh T, Saito Y. Severe hypertriglyceridemia with plasma inhibitory factor(s) on lipoprotein lipase activity in a patient with a common Ser(447)-Ter LPL mutation.  Clin Chim Acta. 2001;  308 139-146
• 18 Shibasaki M, Takahashi K, Itou T, Bujo H, Saito Y. A PPAR agonist improves insulin sensitivity of adipose tissue in mice.  Biochem Biophys Res Commun. 2003;  281 419-423
• 19 Hata A, Ridinger DN, Sutherland SD, Emi M, Kwong LK, Shuhua J, Lubbers A, Guy-Grand B, Basdevant A, Iverius PH. et al . Missense mutations in exon 5 of the human lipoprotein lipase gene. Inactivation correlates with loss of dimerization.  J Biol Chem. 1992;  267 20132-20139
• 20 Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice.  Diabetes. 1988;  37 1163-1167
• 21 Burcelin R, Crivelli V, Dacosta A, Roy-Tirelli A, Thorens B. Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet.  Am J Physiol Endocrinol Metab. 2002;  282 E834-E842
• 22 Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.  Proc Natl Acad Sci USA. 2001;  98 7522-7527
• 23 Ferreira LD, Pulawa LK, Jensen DR, Eckel RH. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance.  Diabetes. 2001;  50 1064-1068
• 24 Voshol PJ, Jong MC, Dahlmans VE, Kratky D, Levak-Frank S, Zechner R, Romijn JA, Havekes LM. In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake.  Diabetes. 2001;  50 2585-2590
• 25 Kitajima S, Morimoto M, Liu E, Koike T, Higaki Y, Taura Y, Mamba K, Itamoto K, Watanabe T, Tsutsumi K, Yamada N, Fan J. Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits.  Diabetologia. 2004;  47 1202-1209
• 26 Liu E, Kitajima S, Higaki Y, Morimoto M, Sun H, Watanabe T, Yamada N, Fan J. High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits.  Metabolism. 2005;  54 132-138

Correspondence