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Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake

Merkel, Martin; Heeren, Jorg; Dudeck, Wiebke; Rinninger, Franz; Radner, Herbert; Breslow, Jan L; Goldberg, Ira J; Zechner, Rudolf; Greten, Heiner
We have previously shown that transgenic expression of catalytically inactive lipoprotein lipase (LPL) in muscle (Mck-N-LPL) enhances triglyceride hydrolysis as well as whole particle lipoprotein and selective cholesterol ester uptake. In the current study, we have examined whether these functions can be performed by inactive LPL alone or require the presence of active LPL expressed in the same tissue. To study inactive LPL in the presence of active LPL in the same tissue, the Mck-N-LPL transgene was bred onto the heterozygous LPL-deficient (LPL1) background. At 18 h of age, Mck-N-LPL reduced triglycerides by 35% and markedly increased muscle lipid droplets. In adult mice, it reduced triglycerides by 40% and increased lipoprotein particle uptake into muscle by 60% and cholesterol ester uptake by 110%. To study inactive LPL alone, the Mck-N-LPL transgene was bred onto the LPL-deficient (LPL0) background. These mice die at approximately 24 h of age. At 18 h of age, in the absence of active LPL, inactive LPL expression did not diminish triglycerides nor did it result in the accumulation of muscle lipid droplets. To study inactive LPL in the absence of active LPL in the same tissue in adult animals, the Mck-N-LPL transgene was bred onto mice that only expressed active LPL in the heart (LPL0/He-LPL). In this case, Mck-N-LPL did not reduce triglycerides or increase the uptake of lipoprotein particles but did increase muscle uptake of chylomicron and very low density lipoprotein cholesterol ester by 40%. Thus, in the presence of active LPL in the same tissue, inactive LPL augments triglyceride hydrolysis and increases whole particle triglyceride-rich lipoprotein and selective cholesterol ester uptake. In the absence of active LPL in the same tissue, inactive LPL only mediates selective cholesterol ester uptake.
PMID: 11751882
ISSN: 0021-9258
CID: 949272

A new piece in the diabetes puzzle

Rossetti, Luciano; Goldberg, Ira J
PMID: 11821890
ISSN: 1078-8956
CID: 949282

Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

Kim, J K; Fillmore, J J; Chen, Y; Yu, C; Moore, I K; Pypaert, M; Lutz, E P; Kako, Y; Velez-Carrasco, W; Goldberg, I J; Breslow, J L; Shulman, G I
Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.
PMCID:34701
PMID: 11390966
ISSN: 0027-8424
CID: 949292

Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues

Lutz, E P; Merkel, M; Kako, Y; Melford, K; Radner, H; Breslow, J L; Bensadoun, A; Goldberg, I J
Lipoprotein lipase (LpL) binding to heparan sulfate proteoglycans (HSPGs) is hypothesized to stabilize the enzyme, localize LpL in specific capillary beds, and route lipoprotein lipids to the underlying tissues. To test these hypotheses in vivo, we created mice expressing a human LpL minigene (hLpL(HBM)) carrying a mutated heparin-binding site. Three basic amino acids in the carboxyl terminal region of LpL were mutated, yielding an active enzyme with reduced heparin binding. Mice expressing hLpL(HBM) accumulated inactive human LpL (hLpL) protein in preheparin blood. hLpL(HBM) rapidly lost activity during a 37 degrees C incubation, confirming a requirement for heparin binding to stabilize LPL: Nevertheless, expression of hLpL(HBM) prevented the neonatal demise of LpL knockout mice. On the LpL-deficient background hLpL(HBM) expression led to defective targeting of lipids to tissues. Compared with mice expressing native hLpL in the muscle, hLpL(HBM) transgenic mice had increased postprandial FFAs, decreased lipid uptake in muscle tissue, and increased lipid uptake in kidneys. Thus, heparin association is required for LpL stability and normal physiologic functions. These experiments confirm in vivo that association with HSPGs can provide a means to maintain proteins in their stable conformations and to anchor them at sites where their activity is required.
PMCID:209279
PMID: 11342582
ISSN: 0021-9738
CID: 952742

Transcytosis of lipoprotein lipase across cultured endothelial cells requires both heparan sulfate proteoglycans and the very low density lipoprotein receptor

Obunike, J C; Lutz, E P; Li, Z; Paka, L; Katopodis, T; Strickland, D K; Kozarsky, K F; Pillarisetti, S; Goldberg, I J
Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of circulating lipoprotein triglyceride molecules, is synthesized in myocytes and adipocytes but functions while bound to heparan sulfate proteoglycans (HSPGs) on the luminal surface of vascular endothelial cells. This requires transfer of LPL from the abluminal side to the luminal side of endothelial cells. Studies were performed to investigate the mechanisms of LPL transcytosis using cultured monolayers of bovine aortic endothelial cells. We tested whether HSPGs and members of the low density lipoprotein (LDL) receptor superfamily were involved in transfer of LPL from the basolateral to the apical side of cultured endothelial cells. Heparinase/heparinitase treatment of the basolateral cell surface or addition of heparin to the basolateral medium decreased the movement of LPL. This suggested a requirement for HSPGs. To assess the role of receptors, we used either receptor-associated protein, the 39-kDa inhibitor of ligand binding to the LDL receptor-related protein and the very low density lipoprotein (VLDL) receptor, or specific receptor antibodies. Receptor-associated protein reduced (125)I-LPL and LPL activity transfer across the monolayers. When the basolateral surface of the cells was treated with antibodies, only anti-VLDL receptor antibodies inhibited transcytosis. Moreover, overexpression of the VLDL receptor using adenoviral-mediated gene transfer increased LPL transcytosis. Thus, movement of active LPL across endothelial cells involves both HSPGs and VLDL receptor.
PMID: 11121409
ISSN: 0021-9258
CID: 1482012

Clinical review 124: Diabetic dyslipidemia: causes and consequences

Goldberg, I J
PMID: 11238470
ISSN: 0021-972x
CID: 949302

Revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association [Guideline]

Krauss, R M; Eckel, R H; Howard, B; Appel, L J; Daniels, S R; Deckelbaum, R J; Erdman, J W Jr; Kris-Etherton, P; Goldberg, I J; Kotchen, T A; Lichtenstein, A H; Mitch, W E; Mullis, R; Robinson, K; Wylie-Rosett, J; St Jeor, S; Suttie, J; Tribble, D L; Bazzarre, T L
PMID: 11208950
ISSN: 0022-3166
CID: 952712

AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association [Guideline]

Krauss, R M; Eckel, R H; Howard, B; Appel, L J; Daniels, S R; Deckelbaum, R J; Erdman, J W Jr; Kris-Etherton, P; Goldberg, I J; Kotchen, T A; Lichtenstein, A H; Mitch, W E; Mullis, R; Robinson, K; Wylie-Rosett, J; St Jeor, S; Suttie, J; Tribble, D L; Bazzarre, T L
PMID: 11062305
ISSN: 0039-2499
CID: 952722

AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association [Guideline]

Krauss, R M; Eckel, R H; Howard, B; Appel, L J; Daniels, S R; Deckelbaum, R J; Erdman, J W Jr; Kris-Etherton, P; Goldberg, I J; Kotchen, T A; Lichtenstein, A H; Mitch, W E; Mullis, R; Robinson, K; Wylie-Rosett, J; St Jeor, S; Suttie, J; Tribble, D L; Bazzarre, T L
PMID: 11056107
ISSN: 0009-7322
CID: 952732

Influence of glucose on production and N-sulfation of heparan sulfate in cultured adipocyte cells

Parthasarathy, N; Gotow, L F; Bottoms, J D; Obunike, J C; Naggi, A; Casu, B; Goldberg, I J; Wagner, W D
Altered lipoprotein lipase regulation associated with diabetes leading to the development of hypertriglyceridemia might be attributed to possible changes in content and the fine structure of heparan sulfate and its associated lipoprotein lipase. Adipocyte cell surface is the primary site of synthesis of lipoprotein lipase and the enzyme is bound to cell surface heparan sulfate proteoglycans via heparan sulfate side chains. In this study, the effect of diabetes on the production of adipocyte heparan sulfate and its sulfation (especially N-sulfation) were examined. Mouse 3T3-L1 adipocytes were exposed to high glucose (25 mM) and low glucose (5.55 mM) in the medium and cell-associated heparan sulfate was isolated and characterized. A significant decrease in total content of heparan sulfate was observed in adipocytes cultured under high glucose as compared to low glucose conditions. The degree of N-sulfation was-assessed through oligosaccharide mapping of heparan sulfate after chemical cleavages involving low pH (1.5) nitrous acid and hydrazinolysis/high pH (4.0) nitrous acid treatments; N-sulfation was found to be comparable between the adipocyte heparan sulfates produced under these glucose conditions. The activity and message levels for N-deacetylase/N-sulfotransferase, the enzyme responsible for N-sulfation in the biosynthesis of heparan sulfate, did not vary in adipocytes whether they were exposed to low or high glucose. While most cells or tissues in diabetic situations produce heparan sulfate with low-charge density concomitant with a decrease in N-sulfation, adipocyte cell system is an exception in this regard. Heparan sulfate from adipocytes cultured in low glucose conditions binds to lipoprotein lipase by the same order of magnitude as that derived from high glucose conditions. It is apparent that adipocytes cultured under high glucose conditions produce diminished levels of heparan sulfate (without significant changes in N-sulfation). In conclusion, it is possible that the reduction in heparan sulfate in diabetes could contribute to the decreased levels of heparan sulfate associated lipoprotein lipase, leading to diabetic hypertriglyceridemia.
PMID: 11129947
ISSN: 0300-8177
CID: 949312