The Experts below are selected from a list of 153954 Experts worldwide ranked by ideXlab platform
Joerg Heeren - One of the best experts on this subject based on the ideXlab platform.
-
apolipoprotein av accelerates plasma hydrolysis of triglyceride rich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
Journal of Biological Chemistry, 2005Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg HeerenAbstract:Abstract Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma Triglycerides. To elucidate the mechanism by which apoAV influences plasma Triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of Triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL Triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
-
apolipoprotein av accelerates plasma hydrolysis of triglyceriderich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
Journal of Biological Chemistry, 2005Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg HeerenAbstract:Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma Triglycerides. To elucidate the mechanism by which apoAV influences plasma Triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of Triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL Triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
Lishin Huang - One of the best experts on this subject based on the ideXlab platform.
-
hepatic overexpression of hormone sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation stimulates direct release of free fatty acids and ameliorates steatosis
Journal of Biological Chemistry, 2008Co-Authors: Brendan N Reid, Gabriele Schoiswohl, Rudolf Zechner, Ira J. Goldberg, Gene P Ables, Oleg A Otlivanchik, William S Blaner, Robert F Schwabe, Streamson C Chua, Lishin HuangAbstract:Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic Triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver Triglycerides by 40–60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-β-hydroxybutyrate levels were increased 3–5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in β-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular Triglycerides could be attributed to increases in β-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.
-
hepatic overexpression of hormone sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation stimulates direct release of free fatty acids and ameliorates steatosis
Journal of Biological Chemistry, 2008Co-Authors: Brendan N Reid, Gabriele Schoiswohl, Rudolf Zechner, Ira J. Goldberg, Gene P Ables, Oleg A Otlivanchik, William S Blaner, Robert F Schwabe, Streamson C Chua, Lishin HuangAbstract:Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic Triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver Triglycerides by 40-60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-beta-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in beta-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular Triglycerides could be attributed to increases in beta-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.
Len A. Pennacchio - One of the best experts on this subject based on the ideXlab platform.
-
Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol
2020Co-Authors: Itamar Grosskopf, Len A. Pennacchio, Edward M. Rubin, Nadine Baroukh, Sung-joon Lee, Yehuda Kamari, Dror Harats, Allen D CooperAbstract:Objective-ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV. Methods and Results-No significant difference in triglyceride production rate was found between apoa5 Ϫ/Ϫ mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14 C-palmitate and 3 H-cholesterol labeled chylomicrons and 125 I-labeled chylomicron remnants, the disappearance of 14 C, 3 H, and 125 I was significantly slower in apoa5 Ϫ/Ϫ mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in apoa5 Ϫ/Ϫ mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in apoa5 Ϫ/Ϫ mice. VLDL from apoa5 Ϫ/Ϫ mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in apoa5 Ϫ/Ϫ mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from apoa5 Ϫ/Ϫ mice. T he level of Triglycerides in the blood has been correlated with the risk of atherosclerosis in a variety of studies. 1,2 Apoproteins of triglyceride-rich lipoproteins (TRL) play an important role in triglyceride transport. In particular, ApoCs and apoE 3,4 strongly affect TRL metabolism and thus plasma triglyceride levels. ApoAV is a newly discovered apolipoprotein, which was identified independently by 2 groups. Conclusions-These ApoAV could influence triglyceride levels through alterations in the hepatic triglyceride secretion rate, or alternatively in the rate of catabolism of Triglycerides within plasma. We report that the presence or absence of apoAV does not affect triglyceride production. The absence of apoAV leads to a reduction in the rate of removal of Triglycerides with the accumulation of larger than normal very-low-density lipoprotein (VLDL) particles in the plasma. These particles are paradoxically worse substrates for lipoprotein lipase than Origina
-
apolipoprotein av accelerates plasma hydrolysis of triglyceride rich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
Journal of Biological Chemistry, 2005Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg HeerenAbstract:Abstract Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma Triglycerides. To elucidate the mechanism by which apoAV influences plasma Triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of Triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL Triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
-
apolipoprotein av accelerates plasma hydrolysis of triglyceriderich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
Journal of Biological Chemistry, 2005Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg HeerenAbstract:Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma Triglycerides. To elucidate the mechanism by which apoAV influences plasma Triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of Triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL Triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
-
mechanism of triglyceride lowering in mice expressing human apolipoprotein a5
Biochemical and Biophysical Research Communications, 2004Co-Authors: Jamila Fruchartnajib, Len A. Pennacchio, E Bauge, Loredanstefan Niculescu, Tatiana Pham, Benoit Thomas, Corinne Rommens, Zouher Majd, Bryan H Brewer, Jean-charles FruchartAbstract:Recently, we reported that apoAV plays key role in Triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limit the elevation of Triglycerides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.
-
apolipoprotein a5 a crucial determinant of plasma triglyceride levels is highly responsive to peroxisome proliferator activated receptor α activators
Journal of Biological Chemistry, 2003Co-Authors: Ngoc Vudac, Len A. Pennacchio, Edward M. Rubin, Bart Staels, Heidelinde Jakel, Maxime Nowak, Philippe Gervois, E Bauge, Helene Dehondt, Jamila FruchartnajibAbstract:The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma Triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor α target gene and support its role as a major mediator for how fibrates reduce plasma Triglycerides in humans.
Jan Boren - One of the best experts on this subject based on the ideXlab platform.
-
kinetic and related determinants of plasma triglyceride concentration in abdominal obesity multicenter tracer kinetic study
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Jan Boren, Niina Matikainen, Sanni Soderlund, Martin Adiels, Gerald F Watts, Dick C Chan, Antti Hakkarainen, Nina Lundbom, Juhani Kahri, B VergesAbstract:Objectives—Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL1) Triglycerides. Approach and Results—A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of Triglycerides and apoB in VLDL1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate (r=0.44, P<0.01; r=0.45, P<0.01) and fractional catabolism (r=0.49, P<0.001; r=0.55, P<0.001) of VLDL1-Triglycerides and VLDL1-apoB. Liver fat mass was independently and directly associated with secretion...
-
kinetic and related determinants of plasma triglyceride concentration in abdominal obesity multicenter tracer kinetic study
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Jan Boren, Niina Matikainen, Sanni Soderlund, Martin Adiels, Gerald F Watts, Dick C Chan, Antti Hakkarainen, Nina Lundbom, Juhani Kahri, B VergesAbstract:Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of VLDL 1 Triglycerides. Approach and Results— A multicentre study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of Triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P r =0.45, P r =0.49, P r =0.55, P 1 -Triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -Triglycerides ( r =0.56, P 1 -apoB ( r =0.53, P 1 -Triglycerides ( r =0.48, P 1 -apoB ( r =0.51, P Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.
-
postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity
Atherosclerosis, 2012Co-Authors: Martin Adiels, Niina Matikainen, Sanni Soderlund, Jukka Westerbacka, Thomas Larsson, Jan Boren, Sven-olof Olofsson, Marja-riitta TaskinenAbstract:Objective To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs. Methods Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and Triglycerides in the very low-density lipoprotein 1 and 2 (VLDL1 and VLDL2) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and Triglycerides in the chylomicron, VLDL1 and VLDL2 fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting. Results Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL1 particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial Triglycerides with less accumulation of apoB100 in the VLDL1 fraction and a faster transfer of apoB100 into the VLDL2 fraction. In contrast, fasting VLDL1 secretion does not predict postprandial triglyceride accumulation. Conclusions Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis.
-
adipocyte differentiation related protein promotes fatty acid storage in cytosolic Triglycerides and inhibits secretion of very low density lipoproteins
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Bjorn Magnusson, Jan Boren, Lennart Asp, Pontus Bostrom, Michel Ruiz, Pia Stillemarkbillton, Daniel Linden, Sven-olof OlofssonAbstract:Objective— We investigated the role of adipocyte differentiation-related protein (ADRP) in triglyceride turnover and in the secretion of very low–density lipoprotein (VLDL) from McA-RH7777 cells and primary rat hepatocytes. Methods and Results— An increase in the expression of ADRP increased triglyceride accumulation in cytosolic lipid droplets and prevented the incorporation of fatty acids into secretable Triglycerides, thereby reducing the secretion of Triglycerides as well as of apolipoprotein B-100 (apoB-100) and apoB-48 VLDL. The ability of ADRP to block the secretion of apoB-100 VLDL1 decreased with increasing quantities of fatty acids in the medium, indicating a saturable process and emphasizing the importance of sequestering of fatty acids for the effect of ADRP on VLDL secretion. Knockdown (small interfering RNA) of ADRP decreased the pool of cytosolic lipid droplets but increased only the secretion of apoB-48 VLDL1. Additionally, there was an increased flow of fatty acids into β-oxidation. Conclusions— ADRP is essential for the accumulation of Triglycerides in cytosolic lipid droplets. An increase in ADRP prevents the formation of VLDL by diverting fatty acids from the VLDL assembly pathway into cytosolic Triglycerides, whereas a decrease of the protein increases the sorting of fatty acids to β-oxidation and promotes the secretion of apoB-48 VLDL1.
James M Ntambi - One of the best experts on this subject based on the ideXlab platform.
-
colocalization of scd1 and dgat2 implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis
Journal of Lipid Research, 2006Co-Authors: Weng Chi Man, Makoto Miyazaki, Kiki Chu, James M NtambiAbstract:Stearoyl-coenzyme A desaturase (SCD) is an endo- plasmic reticulum (ER) protein that catalyzes the D9-cis desaturation of saturated fatty acids. Mice with targeted disruption in SCD1 (Scd1 2/2 ) have significant reduction in the tissue content of Triglycerides, suggesting that mono- unsaturated fatty acids endogenously synthesized by SCD1 are important for triglyceride synthesis. Acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) is the enzyme that catalyzes the final reaction in the synthesis of Triglycerides. The lack of DGAT2, one of the two DGAT isoforms, results in almost a complete loss of tissue Triglycerides. We hy- pothesize that SCD1 participates in triglyceride synthesis by providing a more accessible pool of monounsaturated fatty acids through substrate channeling. In this study, we test whether SCD1 is proximal to DGAT2 by colocalization study with confocal microscopy, coimmunoprecipitation, and fluo- rescence resonance energy transfer using HeLa cells as the model of study. All of the results suggest that SCD1 and DGAT2 are located very close to each other in the ER, which is a very important criterion for the channeling of substrate. By performing subcellular fractionation using mouse liv- ers, we also show, for the first time, that SCD is present in the mitochondria-associated membrane.—Man, W. C., M. Miyazaki, K. Chu, and J. Ntambi. Colocalization of SCD1 and DGAT2: implying preference for endogenous mono- unsaturated fatty acids in triglyceride synthesis. J. Lipid Res. 2006. 47: 1928-1939.
-
a lipogenic diet in mice with a disruption of the stearoyl coa desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis
Journal of Lipid Research, 2001Co-Authors: Makoto Miyazaki, Youngcheul Kim, James M NtambiAbstract:Stearoyl-CoA desaturase (SCD) catalyzes the de novo biosynthesis of oleate and palmitoleate, which are the major fatty acids found in Triglycerides, cholesteryl esters, and phospholipids. A high carbohydrate (lipogenic) diet induces lipogenic gene expression by sterol regulatory element binding protein 1 (SREBP-1c)-mediated gene transcription, leading to an increase in the synthesis of Triglycerides. The lipogenic diet fed to mice with a null mutation in the SCD1 gene (SCD-/-) fails to induce the synthesis of Triglycerides in liver, despite the induction of expression of SREBP-1 and its target genes, fatty acid synthase and glycerol-3-phosphate acyltransferase. The lipogenic diet led to a decrease in the levels of triglyceride, but an increase in the level of cholesteryl esters of saturated fatty acids. Feeding a lipogenic diet supplemented with high levels of oleate to the SCD-/- mice resulted in incorporation of oleate in the liver of SCD-/- mice, but failed to restore Triglycerides to the levels in the normal mouse. Triglyceride synthesis, as measured by the incorporation of [(3)H]glycerol, was dramatically reduced in the liver of SCD-/- mouse fed a lipogenic diet compared with the normal mouse. These observations demonstrate that induction of triglyceride synthesis is highly dependent on SCD1 gene expression.
