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The Role of Lipoprotein Lipase in Adipose Tissue Development and Metabolism

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The Role of Lipoprotein Lipase in Adipose Tissue Development and Metabolism International Journal of Obesity (2000) 24, Suppl 4, S53±S56 ß 2000 Macmillan Publishers Ltd All rights reserved 0307±0565/00 $15.00 www.nature.com/ijo The role of lipoprotein lipase in adipose tissue development and metabolism R Zechner1*, J Strauss1, S Frank2, E Wagner1, W Hofmann1, D Kratky1, M Hiden1 and S Levak-Frank2 1Institute of Molecular Biology, Biochemistry and Microbiology, University of Graz, Graz, Austria; and 2Institute of Medical Biochemistry and Medical Molecular Biology, University of Graz, Graz, Austria Lipoprotein lipase (LPL) is essential for the hydrolysis and distribution of triglyceride-rich lipoprotein-associated fatty acids among extrahepatic tissues. Additionally, the enzyme facilitates several non-lipolysis associated functions including the cellular uptake of whole lipoprotein particles and lipophilic vitamins. The tissue-speci®c variations of LPL expression have been implicated in the pathogenesis of various lipid disorders, obesity and atherosclerosis. Transgenic technology provided the means to study the physiological response to the overexpression or absence of the enzyme in adipose tissue, muscle and macrophages. The effects of varying LPL expression in adipose tissue and muscle are summarized in this article. International Journal of Obesity (2000) 24, Suppl 4, S53±S56 Keywords: lipoprotein lipase; adipose tissue; muscle; transgenic mouse Introduction tant factor in vascular disease as well. The advent of transgenic technology provided the means to directly Fat accumulation in adipose tissue (AT) largely modulate LPL expression levels in mice in a tissue- depends on the ef®cient uptake of fatty acids from dependent manner and study the tissue-speci®c role of the circulation. Since the majority of fatty acids in the enzyme. This article will summarize some of the plasma are present in esteri®ed form as lipoprotein ®ndings that emerged from these studies. associated triglycerides (TG), hydrolysis is a manda- tory initial step for the tissue absorption of free fatty acids (FFA). In peripheral tissues, such as AT, the rate-limiting step for TG catabolism is catalyzed by Disruption of the mouse LPL gene lipoprotein lipase (LPL), an enzyme which is bound to Familial LPL de®ciency is a rare autosomal recessive glucosaminoglycans at the luminal side of the capil- disorder in humans, characterized by a massive accu- lary endothelium. The activity of LPL in AT relative mulation of chylomicrons (type I hyperlipoprotein- to its expression in other tissues, such as skeletal emia).2 Homozygous patients, when not kept under muscle (SM) and cardiac muscle (CM), determines strict dietary control, exhibit plasma triglycerides the in¯ux of FFA and, possibly, the amount of fat above 3000 mg=dl, essentially lack HDL and suffer deposited. LPL is therefore viewed as a `gate keeping' from recurring episodes of pancreatitis. To date more enzyme for the entry and reesteri®cation of FFA in than 80 different mutations within the LPL structural 1 AT. According to this hypothesis, decreased LPL gene are known to cause the disorder. Generally, LPL activity in AT could reduce FFA uptake and lipid de®ciency is not associated with an increased inci- accumulation. Alternatively, overexpression of LPL in dence of atherosclerosis; however, in some families muscle might be associated with the redirection of an increased prevalence of heart disease has been nutrient fats from AT to muscle (`substrate steal'), reported.3 This observation indicated that mutation- again preventing FFA uptake in adipocytes. It is speci®c variations exist with regard to atherosclerosis likely, therefore, that LPL and its tissue-speci®c susceptibility. Interestingly, patients with LPL de®- regulation are centrally involved in the pathogenesis ciency have normal amounts of AT, suggesting alter- of obesity. In addition, LPL plays a key role in the native, LPL-independent pathways to accumulate TG metabolism of lipoproteins, which makes it an impor- in adipocytes.4 Several years ago two laboratories reported indepen- dently the generation of LPL knock-out mice.5,6 Homo- *Correspondence: R Zechner, Institute of Molecular Biology, zygous LPL-de®cient animals also developed severe Biochemistry and Microbiology, University of Graz, Heinrichstrasse 31a, 8010 Graz, Austria. hypertriglyceridemia, hypercholesterolemia and low E-mail: [email protected] HDL, but in contrast to humans all knock-out animals Lipoprotein lipase in adipose tissue development R Zechner et al S54 died within 30 h after birth. This phenotype was SM and the uptake of a-tocopherol, providing in vivo similar to the one observed in the well-studied evidence for the involvement of LPL in cellular cld=cld-mouse, namely severe hypertriglyceridemia vitamin E uptake. and post-natal death as a result of the de®ciency of enzymatically active LPL and hepatic lipase.7 Both mouse models, cld=cld and LPL knock-out, suggested that LPL-de®cient mice, in contrast to humans, cannot Cardiac muscle tolerate the massive amount of TG that accumulates in LPL overexpression in cardiac muscle (CM) was the blood as soon as the newborn animals begin to achieved by the fusion of the LPL minigene with suckle. Although the exact cause of death has not been promoter sequences from the mouse LPL gene.14 elucidated, it has been speculated that the excessive Eight kilobases (kb) of 50 ¯anking region of the blood-lipid content could clog the lung capillaries and mouse LPL gene were suf®cient for CM-speci®c interfere with a functional gas exchange, resulting in LPL expression, but were unable to drive transgene alveolar dysfunction and cyanosis.5 Hypoglycemia transcription in SM or AT. Even moderate levels of was proposed as an alternative cause of death by CM-speci®c LPL overexpression had a pronounced Merkel et al,8 when the authors observed that new- effect on VLDL catabolism and plasma TG levels, born LPL knock-out mice had unusually low blood indicating a particularly powerful role of CM-LPL in glucose levels. Recent experiments in our laboratory the catabolism of TG-rich lipoproteins. utilizing the transient post-natal adenovirus mediated expression of LPL has enabled us to rescue LPL knock-out mice during the suckling period and gen- erate adult, LPL-de®cient animals to an age well over Liver 12 months. These mice exhibited increased TG levels, Liver-speci®c overexpression of LPL was achieved by extremely low HDL concentrations and increased the fusion of the minigene with the promoter for FFA and ketones in plasma when kept on a chow apolipoprotein AI.8 Despite a 4 ± 9-fold overexpres- diet. Gross morphological examination revealed the sion of the human enzyme in the liver, the effects on presence of roughly normal amounts of AT. plasma lipids and liver lipid accumulation were quite moderate. Interestingly, however, these animals exhibited a marked increase in plasma ketones in response to increased FFA uptake in the liver. Tissue-speci®c overexpression of LPL Tissue-speci®c LPL transgene Skeletal muscle LPL overexpression in skeletal muscle (SM) was expression on an LPL knock-out achieved by fusing an LPL minigene to the promoter background of the mouse muscle creatine kinase gene.9±11 A5- fold overexpression of LPL in SM caused a marked Crossbreeding of tissue-speci®c LPL overexpressing decrease in TG rich lipoproteins, decreased HDL transgenic animals with heterozygous LPL knock-out levels, and low plasma FFA concentrations.9,10 The animals resulted in mice that expressed only the work by Jensen et al10 provided convincing evidence transgene but not the endogenous LPL gene. Depend- that low-level overexpression of LPL in SM can ing on the tissue of transgene expression, these ani- decrease a diet-induced weight gain in agreement mals produced LPL activity only in SM, CM or liver with the `substrate steal' concept. Higher levels of but lacked the enzyme in all other tissues, including LPL overexpression, however, resulted in the pro- AT and macrophages. Independent of the site of LPL liferation of mitochondria and peroxisomes in SM, expression, all mouse lines were rescued from the which eventually led to a severe myopathy and pre- lethal hypertriglyceridemia present in LPL knock-out mature death.9 These experiments indicated that TG mice. This ®nding indicated that LPL expression in hydrolysis by SM-LPL and the subsequent uptake of any one of these tissues is adequate for survival. the FFA by muscle tissue is very ef®cient. The Conversely, complete loss of LPL expression in any apparently unrestricted FFA uptake that leads to of these tissues does not cause lethality. In fact, all of myopathy suggested that LPL is the major determi- the above mouse lines remain grossly healthy and nant for FFA uptake in muscle and that no additional have a normal life expectancy. Additionally, LPL regulatory mechanism exists to prevent the ultimately activity measurements in various tissues of these lethal FFA accumulation in SM. `single tissue' expressors demonstrated that LPL pre- Muscle-speci®c LPL overexpression in transgenic dominantly remains in the tissue where it was origin- mice also enabled an investigation of the role of LPL ally synthesized. No evidence was obtained for the in the uptake of apolar lipids (cholesteryl esters) and translocation of a considerable amount of enzymati- lipophilic vitamins (vitamin E).12,13 A clear linear cally active enzyme from the site of synthesis to other relationship was observed between LPL activity in tissues. International Journal of Obesity Lipoprotein lipase in
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