ATHEROSCLEROSIS UPDATE
ATHEROSCLEROSE: LE POINT Canadian Atherosclerosis Society / Societe canadienne d'atherosclerose
Tissue-specific regulation of lipoprotein lipase Janice E.A. Braun, PhD; David L. Severson, PhD
L ipoprotein lipase (LPL) hydrolyses the triglyceride component of circulating lipoprotein particles, chylomicrons and very-low-density lipoproteins to provide fatty acids for tissue use. The enzyme is found in adipose tissue, cardiac and skeletal muscle, lactating mammary gland, lung, spleen and brain,' where it catalyses the rate-controlling step for lipid acquisition from circulating triglycerides. It thus plays a key role in normal fuel metabolism; accordingly, familial LPL deficiency produces profound hypertriglyceridemia. In addition, the regulation of LPL is important in disorders of lipid metabolism associated with obesity and diabetes mellitus. Although LPL is encoded by a single gene, its activity is regulated in a tissue-specific manner. For example, with fasting, LPL activity decreases in adipose tissue but increases in cardiac tissue; as a result, triglyceride fatty acids are diverted away from storage to meet the metabolic demands of the heart.' In contrast, a 6-hour insulin and glucose infusion given to normal-weight fasting subjects caused LPL activity to increase threefold in adipose tissue but to decrease significantly in skeletal muscle.2 Therefore, insulin directs triglyceride fatty acids away from muscle oxidation and toward storage. Patients with poorly controlled diabetes have decreased adipose tissue LPL activity, which accounts in part for their hypertriglyceridemia; therapy with insulin or glyburide increases LPL activity and immunoreactive mass in adipose tissue.3 LPL activity is greater in gluteal adipose tissue than in abdominal adipose tissue in premenopausal women of normal weight;45 the opposite pattern is
observed in men.4 Thus, regional differences in adipose tissue LPL activity may underlie variations in body fat deposition. In obese women LPL activity is markedly increased in both gluteal and abdominal adipose tissue to values that are no longer different.5 The extent of the increase in LPL activity in the two regions after an insulin and glucose infusion is the same for normal-weight and obese women.5 Tissue-specific regulation of LPL is physiologically important because it directs the use of triglyceride fatty acids according to metabolic demands. The underlying cellular mechanisms remain enigmatic. Control of LPL gene expression by specific DNA binding elements is likely important along with regulation at other sites in the biosynthetic pathway for LPL.' In human adipose tissue the stimulation of LPL activity by insulin therapy is associated with increased synthesis of LPL protein but no change in LPL messenger RNA levels, which suggests hormonal regulation of translation.3
References 1. Braun JEA, Severson DL: Regulation of the synthesis, processing and translocation of lipoprotein lipase. Biochem J (in press) 2. Farese RV, Yost TJ, Eckel RH: Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans. Metabolism 1991; 40: 214-216 3. Simsolo RB, Ong JM, Saffari B et al: Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. J Lipid Res 1992; 33: 89-95 4. Amer P, Lithell H, Wahrenberg H et al: Expression of lipoprotein lipase in different human subcutaneous adipose tissue regions. JLipid Res 1991; 32: 423-429 5. Yost TJ, Eckel RH: Regional similarities in the metabolic regulation of adipose tissue lipoprotein lipase. Metabolism 1992; 41: 33-36
Dr. Braun is with the Department ofGastroenterology, Stanford University School ofMedicine, Stanford, Calif Dr. Severson is professor ofpharmacology and therapeutics at the University of Calgary, Calgary, Alta.
This article was made possible by an educational grant to the Canadian Atherosclerosis Society (CAS) from Merck Frosst Canada Inc., but the authors and the content of the article were determined solely by the CAS. The opinions expressed herein are those of the authors and not necessarily those of the CAS. Reprint requests to: Dr. David L. Severson, MRC Signal Transduction Group, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4NI 1192
CAN MED ASSOCJ 1992; 147(8)
LE 15 OCTOBRE 1992
ATHEROSCLEROSE: LE POINT Canadian Atherosclerosis Society / Societe canadienne d'atherosclerose
Tissue-specific regulation of lipoprotein lipase Janice E.A. Braun, PhD; David L. Severson, PhD
L ipoprotein lipase (LPL) hydrolyses the triglyceride component of circulating lipoprotein particles, chylomicrons and very-low-density lipoproteins to provide fatty acids for tissue use. The enzyme is found in adipose tissue, cardiac and skeletal muscle, lactating mammary gland, lung, spleen and brain,' where it catalyses the rate-controlling step for lipid acquisition from circulating triglycerides. It thus plays a key role in normal fuel metabolism; accordingly, familial LPL deficiency produces profound hypertriglyceridemia. In addition, the regulation of LPL is important in disorders of lipid metabolism associated with obesity and diabetes mellitus. Although LPL is encoded by a single gene, its activity is regulated in a tissue-specific manner. For example, with fasting, LPL activity decreases in adipose tissue but increases in cardiac tissue; as a result, triglyceride fatty acids are diverted away from storage to meet the metabolic demands of the heart.' In contrast, a 6-hour insulin and glucose infusion given to normal-weight fasting subjects caused LPL activity to increase threefold in adipose tissue but to decrease significantly in skeletal muscle.2 Therefore, insulin directs triglyceride fatty acids away from muscle oxidation and toward storage. Patients with poorly controlled diabetes have decreased adipose tissue LPL activity, which accounts in part for their hypertriglyceridemia; therapy with insulin or glyburide increases LPL activity and immunoreactive mass in adipose tissue.3 LPL activity is greater in gluteal adipose tissue than in abdominal adipose tissue in premenopausal women of normal weight;45 the opposite pattern is
observed in men.4 Thus, regional differences in adipose tissue LPL activity may underlie variations in body fat deposition. In obese women LPL activity is markedly increased in both gluteal and abdominal adipose tissue to values that are no longer different.5 The extent of the increase in LPL activity in the two regions after an insulin and glucose infusion is the same for normal-weight and obese women.5 Tissue-specific regulation of LPL is physiologically important because it directs the use of triglyceride fatty acids according to metabolic demands. The underlying cellular mechanisms remain enigmatic. Control of LPL gene expression by specific DNA binding elements is likely important along with regulation at other sites in the biosynthetic pathway for LPL.' In human adipose tissue the stimulation of LPL activity by insulin therapy is associated with increased synthesis of LPL protein but no change in LPL messenger RNA levels, which suggests hormonal regulation of translation.3
References 1. Braun JEA, Severson DL: Regulation of the synthesis, processing and translocation of lipoprotein lipase. Biochem J (in press) 2. Farese RV, Yost TJ, Eckel RH: Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans. Metabolism 1991; 40: 214-216 3. Simsolo RB, Ong JM, Saffari B et al: Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. J Lipid Res 1992; 33: 89-95 4. Amer P, Lithell H, Wahrenberg H et al: Expression of lipoprotein lipase in different human subcutaneous adipose tissue regions. JLipid Res 1991; 32: 423-429 5. Yost TJ, Eckel RH: Regional similarities in the metabolic regulation of adipose tissue lipoprotein lipase. Metabolism 1992; 41: 33-36
Dr. Braun is with the Department ofGastroenterology, Stanford University School ofMedicine, Stanford, Calif Dr. Severson is professor ofpharmacology and therapeutics at the University of Calgary, Calgary, Alta.
This article was made possible by an educational grant to the Canadian Atherosclerosis Society (CAS) from Merck Frosst Canada Inc., but the authors and the content of the article were determined solely by the CAS. The opinions expressed herein are those of the authors and not necessarily those of the CAS. Reprint requests to: Dr. David L. Severson, MRC Signal Transduction Group, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4NI 1192
CAN MED ASSOCJ 1992; 147(8)
LE 15 OCTOBRE 1992
