Lipoprotein Lipase and Obesity
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Vol.4, No.12A, 1405-1412 (2012) Health http://dx.doi.org/10.4236/health.2012.412A203 Lipoprotein lipase and obesity Masataka Kusunoki1*, Kazuhiko Tsutsumi2, Daisuke Sato3, Takao Nakamura3 1Department of Internal Medicine, Medical Clinic, Aichi Medical University, Nagoya, Japan; *Corresponding Author: [email protected] 2Okinaka Memorial Institute for Medical Research, Tokyo, Japan 3Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, Yamagata, Japan Received 11 October 2012; revised 11 November 2012; accepted 24 November 2012 ABSTRACT stored in adipose tissue. The balance between these competing effects could determine whether increased Obesity is one of the fast-growing major dis- LPL activity will lead to a reduced rate of weight gain or eases in developed and developing countries. to increased adiposity through increased rates of adipose As has been persuasively argued, long-term tissue storage of TG. An imbalance of LPL activity may imbalance between intake and expenditure of fat alter the partitions of plasma TG between muscle and is a central factor in the etiology of obesity. adipose tissue, and thus influence insulin resistance and Obesity aggravates insulin resistance and pro- obesity. motes cardiovascular diseases and atheroscle- Institute of Otsuka Pharmaceutical Factory, Inc. syn- rosis. We hypothesized that elevating lipopro- thesized the LPL activator NO-1886 ([4-(4-bromo-2- tein lipase (LPL) activity in skeletal muscle cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl would cause an improvement of obesity. To test ester, CAS no.: 133208-93-2, generic name: ibrolipim). this hypothesis, we studied the effects of the Hara et al. reported that LPL activator NO-1886 LPL activator NO-1886 in obese animals. NO- treatment in high-fructose diet induced insulin resistance 1886 elevated LPL activity in skeletal muscle, rats decreases the respiratory quotient (RQ) and plasma and improved obesity as well as insulin resis- TG [3]. These results may indicate the elevation of LPL tance in obese rats. Furthermore, NO-1886 miti- activity ameliorate obesity. gated body weight gain induced by pioglitazone Therefore, we hypothesized that elevating LPL activity without suppressive effect on the adiponectin- would cause an improvement of obesity. To test this hy- increasing action of pioglitazone. LPL activators pothesis, we studied the effects of the LPL activator hold a lot of promise of curing several diseases NO-1886 in obese animals. shown above in clinical scene. 2. BACKGROUND OF LIPOPROTEIN Keywords: Lipoprotein Lipase; Lipoprotein Lipase LIPASE Activator; Insulin Resistance; Lipid Metabolism LPL is a glycoprotein located on the luminal surface of capillary endothelial cells. The active enzyme is a non- 1. INTRODUCTION convalent homodimer [4]. The enzyme has an apparent Obesity in adulthood is characterized by adipocyte monometric molecular mass of 60,000 daltons on SDS- hypertrophy. Adipose tissue participates in the regulation PAGE. The human LPL gene is approximately 30 kb in of energy homeostasis. High-fat diet-induced insulin length [5]. resistance associated with obesity is a major risk factor LPL mRNA has been found in human adipose tissue, for diabetes and cardiovascular disease [1]. Adipose tis- and also in muscle, adrenal, kidneys, intestine and neo- sue itself serves as the site of triglyceride (TG) storage natal, but not adult liver. The mRNA for LPL in humans and free fatty acid release in response to changing energy is highly homologus with that of mice, rats and cows [6, demands [1]. 7]. Lipoprotein lipase (LPL) plays a pivotal role in lipids LPL binds to heparin sulfate on the surface of endo- and the metabolism of lipoprotein [2]. Major functions of thelial cells via the heparin-binding site, which allows LPL include the hydrolysis of TG-rich lipoproteins and the enzyme to be extended into the plasma [8,9]. Fol- release of non-esterified fatty acid (NEFA), which are lowing intravenous administration of heparin, LPL can taken up and used for metabolic energy in peripheral be displaced from the endothelial surface into plasma tissue such as muscle, or are re-esterified into TG and (post-heparin plasma), where enzyme activity can be Copyright © 2012 SciRes. OPEN ACCESS 1406 M. Kusunoki et al. / Health 4 (2012) 1405-1412 measured. The active enzyme bound to heparin sulfate HDL-C concentrations and results in a significant de- on the capillary endothelium is predominantly in the crease in LPL catalytic activity [18]. They showed the dimeric form. relationship between LPL activity and plasma HDL-C TG and monoglyceride are preferred substrates for concentrations, and suggested that a specific LPL muta- LPL, which preferentially hydrolyzes 1- and 3-ester tion may be a factor in the development of atherosclero- bounds in TG, generating 2-monoglyceride, which are sis. converted to 1-monoglyceride by isomerization for fur- Higher levels of postheparin plasma LPL activity are ther hydrolysis [10]. associated with decrease plasma TG and increased A small portion of the core TG from chylomicron and HDL-C [13]. People who are heterozygous for LPL defi- very-low-density lipoprotein (VLDL) can be transferred ciency have increased plasma TG and decreased plasma to high-density lipoprotein (HDL). More important con- HDL-C concentrations, a profile associated with in- tributors to HDL are the surface remnants of the TG-rich creased atherogenic risk [19]. These reports suggest that lipoproteins that occur as a result of hydrolysis of core increased postheparin plasma LPL activity is associated TG. Nikkila et al. noted a relationship between LPL ac- with protection against atherosclerosis in humans. tivity and HDL cholesterol (HDL-C), especially HDL2 Fan et al. generated transgenic rabbits expressing hu- cholesterol (HDL2-C), in many clinical situations [11], man LPL to elucidate the physiological roles of LPL in and recently, we demonstrated that activation of LPL lipid and lipoprotein metabolism. When the transgenic causes production of HDL2-C by catabolism of TG-rich rabbits were fed a cholesterol-rich diet, the development lipoproteins and enlarges HDL2 particle size in rats [12]. of hypercholesterolemia and aortic atherosclerosis was Tsutsumi et al. reported that plasma TG levels were in- dramatically suppressed [20]. Using another model, versely correlated with postheparin plasma LPL activity, Shimada et al. established an overexpressed human LPL while HDL-C levels were positively correlated with the gene in the heart, skeletal muscle, and adipose tissue of activity of the enzyme in rats [13]. mice. These transgenic mice had 5- and 1.7-fold higher Insulin increases LPL activity, rates of LPL synthesis LPL activity in adipose tissue and postheparin plasma, and LPL mRNA levels in adipocytes [14]. Since insulin respectively. Also, VLDL triglycerides were greatly re- does not stimulate LPL gene transcription [4], the in- duced and HDL2 was increased 1.4-fold [21]. These re- creases in steady-state LPL mRNA must be due to sults demonstrated that the lipid profile in these LPL changes in mRNA stability (post-transcriptional mecha- transgenic mice is antiatherogenic. nism). Shimada et al. also created low density lipoprotein Insulin-deficient diabetes results in a reduced degrada- (LDL) receptor knockout mice (LDLRKO) that over ex- tion of VLDL by the reduction of functional (endothe- pressd LPL (LPL/LDLRKO) by mating LPL transgenic lium-bound) LPL activity in myocardium and adipose mice to LDLRKO mice, and compared their plasma tissue. And short-term administration of insulin in vivo lipoprotein profiles and atherosclerosis with those in non restores the effects of LPL activity in adipose tissue, but expressing LDLRKO mice. LPL/LDLRKO mice showed not in myocardium [15]. marked suppression of mean plasma TG concentrations Whether LPL directly or indirectly promotes or pro- and a modest decrease in cholesterol concentrations tects against atherosclerosis remains controversial. Mi- compared to LDLRKO mice. Additionally, larger lipo- senbock et al. reported that LPL +/− humans have protein particles of intermediate density lipoprotein/LDL, atherogenic lipoproteins, especially in the postprandial which is considered remnant lipoproteins, were selec- state [16]. Katzel et al. found that older, normocholes- tively reduced in LPL/LDLRKO mice. Therefore, it was terolemic, nondiabetic athletic individuals with silent showed that the altered lipoprotein profile, in particular myocardial ischemia have increased insulin resistance, the reduced level of remnant lipoproteins, plays a role for increased postheparin plasma hepatic triglyceride lipase protection by LPL against atherosclerosis [22]. (HTGL) activity, and reduced postprandial response of Regarding the LPL activator NO-1886, NO-1886 were abdominal adipose tissue LPL activity to feeding [17]. significantly dose-dependent increases in postheparin These conditions are associated with low HDL2-C levels plasma LPL activity in normal rats. On the other hand, and increased postprandial lipemia. The abnormalities in NO-1886 did not affect postheparin plasma HTGL. NO- plasma HDL-C and postprandial TG metabolism may 1886 also significantly and dose-dependently increased increase the risk for coronary artery disease in these sub- tissue LPL activity in normal rats. NO-1886 enhanced jects. expression of LPL mRNA in adipose tissue and myocar- Reymer et al. studied human LPL mutations. They dium, and increased LPL protein mass and LPL activity