The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
M. Mahmood Hussain - One of the best experts on this subject based on the ideXlab platform.
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Circadian regulators of intestinal Lipid Absorption
Journal of lipid research, 2014Co-Authors: M. Mahmood Hussain, Xiaoyue PanAbstract:Among all the metabolites present in the plasma, Lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These Lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in Lipid Absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circadian clock genes and these genes might control circadian expression of different proteins involved in intestinal Lipid Absorption. Intestinal circadian clock genes are synchronized by signals emanating from the suprachiasmatic nuclei that constitute a master clock and from signals coming from other environmental factors, such as food availability. Disruptions in central clock, as happens due to disruptions in the sleep/wake cycle, affect intestinal function. Similarly, irregularities in temporal food intake affect intestinal function. These changes predispose individuals to various metabolic disorders, such as metabolic syndrome, obesity, diabetes, and atherosclerosis. Here, we summarize how circadian rhythms regulate microsomal triglyceride transfer protein, apoAIV, and nocturnin to affect diurnal regulation of Lipid Absorption.
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Intestinal Lipid Absorption and lipoprotein formation.
Current opinion in lipidology, 2014Co-Authors: M. Mahmood HussainAbstract:Purpose of review To summarize the evidence for the presence of two Lipid Absorption pathways and their regulation. Recent findings Lipid Absorption involves hydrolysis of dietary fat in the lumen of the intestine, followed by the uptake of hydrolyzed products by enterocytes. Lipids are resynthesized in the endoplasmic reticulum and are either secreted with chylomicrons and HDLs or stored as cytoplasmic Lipid droplets. Lipids in the droplets are hydrolyzed and are secreted at a later time. Secretion of Lipids by the chylomicron and HDL pathways are dependent on microsomal triglyceride transfer protein (MTP) and ATP-binding cassette family A protein 1, respectively, and are regulated independently. Gene-ablation studies showed that MTP function and chylomicron assembly is essential for the Absorption of triglycerides. Ablation of MTP abolishes triglyceride Absorption and results in massive triglyceride accumulation in enterocytes. Although the majority of phosphoLipid, cholesterol, and vitamin E are absorbed through the chylomicron pathway, a significant amount of these Lipids are also absorbed via the HDL pathway. Chylomicron assembly and secretion is increased by the enhanced availability of fatty acids, whereas the HDL pathway is upregulated by liver X receptor agonists. Summary Triglycerides are exclusively transported with chylomicrons and this process is critically dependent on MTP. In addition to chylomicrons, Absorption of phosphoLipids, free cholesterol, retinol, and vitamin E also involves HDLs. These two pathways are complementary and are regulated independently. They may be targeted to lower Lipid Absorption in order to control hyperLipidemia, obesity, metabolic syndrome, steatosis, insulin resistance, atherosclerosis, and other disorders.
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Abstract 2: Circadian Regulation of Intestinal Lipid Absorption by ApoAIV Involves Forkhead Transcription Factors A2/O1 and MTP
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, M. Mahmood HussainAbstract:Clock, MTP and nocturnin are involved in the circadian regulation of intestinal Lipid Absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma Lipids and intestinal Lipid Absorption in mice. Total plasma triglyceride/cholesterol in ApoAIV-/- mice showed diurnal variations similar to ApoAIV+/+ mice; however, increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV-/- mice absorbed fewer Lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night and its induction after food entrainment was less in ApoAIV-/- mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2/FoxO1 transcription factors and their binding to the identified cis -elements in the MTP promoter at night. Knockdown of FoxA2/FoxO1 abolished apoAIV mediated MTP induction. Moreover, FoxA2/FoxO1 expression showed diurnal variations and their expressions were significantly lower in ApoAIV-/- mice. These data indicate that apoAIV modulates diurnal regulation of Lipid Absorption by regulating forkhead transcription factors and MTP, and that inhibition of apoAIV expression might reduce plasma Lipids.
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Clock regulation of dietary Lipid Absorption.
Current opinion in clinical nutrition and metabolic care, 2012Co-Authors: M. Mahmood Hussain, Xiaoyue PanAbstract:Purpose of reviewTo summarize the new knowledge about the regulation of dietary Lipid Absorption by circadian locomotor output cycles kaput (Clock) and Nocturnin.Recent findingsRecent findings have shown that Clock and Nocturnin, proteins involved in circadian regulation, play an important role in t
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An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and Lipid Absorption
Journal of Lipid Research, 2010Co-Authors: Jahangir Iqbal, Benny Hung-junn Chang, Streamson C. Chua, Lawrence Chan, Xiaosong Li, Gary J Schwartz, M. Mahmood HussainAbstract:Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and Lipid Absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and Lipid Absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal Lipid Absorption.
Wendong Huang - One of the best experts on this subject based on the ideXlab platform.
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1942-P: Vertical Sleeve Gastrectomy Confers Metabolic Improvements by Reducing Intestinal Bile Acids and Lipid Absorption in Mice
Diabetes, 2020Co-Authors: Lili Ding, Jingyan Tian, Wendong HuangAbstract:Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the mechanisms through which changes in BA content and signaling contribute to the metabolic effects of VSG remain poorly understood. Therefore, in this study, we aim to systematically evaluate the roles of FXR in VSG and determine the underlying mechanism by which bile acids mediate the beneficial effects of VSG. Our data demonstrated that both intestine- and liver-specific farnesoid X receptor (Fxr) knockout mice retained VSG effects and VSG did not appear to increase FXR activation in the liver or intestine, indicating that hepatic or intestinal FXR is dispensable for the metabolic improvement of VSG. We further found that VSG altered gut microbiota composition and reduced intestinal BA levels in mice, resulting in lower intestinal fat Absorption and concomitant metabolic improvements similar to those observed in Fxr null mice. We then confirmed these findings in sterol 27-hydroxylase knockout (Cyp27a1-/-) mice, which exhibited low intestinal BAs and fat Absorption, did not experience metabolic improvements after VSG. Our findings reveal that reductions in intestinal BAs and Lipid Absorption may underlie the metabolic benefits of VSG. Disclosure L. Ding: None. J. Tian: None. W. Huang: None. Funding NCIR01CA139158; Schaeffer Foundation (to W.H.); Hench Foundation (to W.H.); National Natural Science Foundation of China (81773961); Shanghai Pujiang Program (17PJ1408800 to L.D.)
Mahmood M Hussain - One of the best experts on this subject based on the ideXlab platform.
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prap1 is a novel Lipid binding protein that promotes Lipid Absorption by facilitating mttp mediated Lipid transport
Journal of Biological Chemistry, 2021Co-Authors: Hubert W Peng, Tzuyuan Chiu, Yujen Liang, Chiajen Lee, Chihsyuan Liu, Chingshu Suen, Jeffrey J Y Yen, Hungta Chen, Mingjing Hwang, Mahmood M HussainAbstract:Microsomal triglyceride transfer protein (MTTP) is an endoplasmic reticulum resident protein that is essential for the assembly and secretion of triglyceride (TG)-rich, apoB-containing lipoproteins. Although the function and structure of mammalian MTTP have been extensively studied, how exactly MTTP transfers Lipids to Lipid acceptors and whether there are other biomolecules involved in MTTP-mediated Lipid transport remain elusive. Here we identify a role in this process for the poorly characterized protein PRAP1. We report that PRAP1 and MTTP are partially colocalized in the endoplasmic reticulum. We observe that PRAP1 directly binds to TG and facilitates MTTP-mediated Lipid transfer. A single amino acid mutation at position 85 (E85V) impairs PRAP1's ability to form a ternary complex with TG and MTTP, as well as impairs its ability to facilitate MTTP-mediated apoB-containing lipoprotein assembly and secretion, suggesting that the ternary complex formation is required for PRAP1 to facilitate MTTP-mediated Lipid transport. PRAP1 is detectable in chylomicron/VLDL-rich plasma fractions, suggesting that MTTP recognizes PRAP1-bound TG as a cargo and transfers TG along with PRAP1 to Lipid acceptors. Both PRAP1-deficient and E85V knock-in mutant mice fed a chow diet manifested an increase in the length of their small intestines, likely to compensate for challenges in absorbing Lipid. Interestingly, both genetically modified mice gained significantly less body weight and fat mass when on high-fat diets compared with littermate controls and were prevented from hepatosteatosis. Together, this study provides evidence that PRAP1 plays an important role in MTTP-mediated Lipid transport and Lipid Absorption.
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prap1 is a novel Lipid binding protein that promotes Lipid Absorption by facilitating mttp mediated Lipid transport
Journal of Biological Chemistry, 2020Co-Authors: Hubert W Peng, Tzuyuan Chiu, Yujen Liang, Chiajen Lee, Chihsyuan Liu, Chingshu Suen, Jeffrey J Y Yen, Hungta Chen, Mingjing Hwang, Mahmood M HussainAbstract:Microsomal triglyceride transfer protein (MTTP) is an endoplasmic reticulum (ER) resident protein that is essential for the assembly and secretion of triglyceride (TG)-rich, apoB-containing lipoproteins. Although the function and structure of mammalian MTTP have been extensively studied, how exactly MTTP transfers Lipids to Lipid acceptors and whether there are other biomolecules involved in MTTP-mediated Lipid transport remain elusive. Here we identify a role in this process for the poorly characterized protein PRAP1. We report that PRAP1 and MTTP are partially co-localized in the ER. We observe that PRAP1 directly binds to TG and facilitates MTTP-mediated Lipid transfer. A single amino acid mutation at position 85 (E85V) impairs PRAP1's ability to form a ternary complex with TG and MTTP, as well as impairs its ability to facilitate MTTP-mediated apoB-containing lipoprotein assembly and secretion, suggesting that the ternary complex formation is required for PRAP1 to facilitate MTTP-mediated Lipid transport. PRAP1 is detectable in chylomicron/VLDL-rich plasma fractions, suggesting that MTTP recognizes PRAP1-bound TG as a cargo and transfers TG along with PRAP1 to Lipid acceptors. Both PRAP1 deficient and the E85V knock-in mutant mice fed a chow diet manifested an increase in the length of their small intestines, likely to compensate for challenges in absorbing Lipid. Interestingly, both genetically modified mice gained significantly less body weight and fat mass when on high fat diets compared to littermate controls and were prevented from hepatosteatosis. Together, this study provides evidence that PRAP1 plays an important role in MTTP-mediated Lipid transport and Lipid Absorption.
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Lipid Absorption defects in intestine specific microsomal triglyceride transfer protein and atp binding cassette transporter a1 deficient mice
Journal of Biological Chemistry, 2013Co-Authors: Jahangir Iqbal, John S Parks, Mahmood M HussainAbstract:We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol Absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol Absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol Absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92–95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride Absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular Lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for Lipid Absorption and are the main determinants of plasma and intestinal Lipid levels. Reducing their activities might lower plasma Lipid concentrations.
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circadian regulation of intestinal Lipid Absorption by apolipoprotein aiv involves forkhead transcription factors a2 and o1 and microsomal triglyceride transfer protein
Journal of Biological Chemistry, 2013Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, Mahmood M HussainAbstract:Abstract We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal Lipid Absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma Lipids and intestinal Lipid Absorption in mice. Plasma triglyceride in apoAIV−/− mice showed diurnal variations similar to apoAIV+/+ mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV−/− mice absorbed fewer Lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV−/− mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between −204/−775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV−/− mice. These data indicate that apoAIV modulates diurnal changes in Lipid Absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma Lipids.
Jahangir Iqbal - One of the best experts on this subject based on the ideXlab platform.
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Lipid Absorption defects in intestine specific microsomal triglyceride transfer protein and atp binding cassette transporter a1 deficient mice
Journal of Biological Chemistry, 2013Co-Authors: Jahangir Iqbal, John S Parks, Mahmood M HussainAbstract:We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol Absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol Absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol Absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92–95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride Absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular Lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for Lipid Absorption and are the main determinants of plasma and intestinal Lipid levels. Reducing their activities might lower plasma Lipid concentrations.
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circadian regulation of intestinal Lipid Absorption by apolipoprotein aiv involves forkhead transcription factors a2 and o1 and microsomal triglyceride transfer protein
Journal of Biological Chemistry, 2013Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, Mahmood M HussainAbstract:Abstract We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal Lipid Absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma Lipids and intestinal Lipid Absorption in mice. Plasma triglyceride in apoAIV−/− mice showed diurnal variations similar to apoAIV+/+ mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV−/− mice absorbed fewer Lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV−/− mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between −204/−775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV−/− mice. These data indicate that apoAIV modulates diurnal changes in Lipid Absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma Lipids.
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Abstract 2: Circadian Regulation of Intestinal Lipid Absorption by ApoAIV Involves Forkhead Transcription Factors A2/O1 and MTP
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, M. Mahmood HussainAbstract:Clock, MTP and nocturnin are involved in the circadian regulation of intestinal Lipid Absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma Lipids and intestinal Lipid Absorption in mice. Total plasma triglyceride/cholesterol in ApoAIV-/- mice showed diurnal variations similar to ApoAIV+/+ mice; however, increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV-/- mice absorbed fewer Lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night and its induction after food entrainment was less in ApoAIV-/- mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2/FoxO1 transcription factors and their binding to the identified cis -elements in the MTP promoter at night. Knockdown of FoxA2/FoxO1 abolished apoAIV mediated MTP induction. Moreover, FoxA2/FoxO1 expression showed diurnal variations and their expressions were significantly lower in ApoAIV-/- mice. These data indicate that apoAIV modulates diurnal regulation of Lipid Absorption by regulating forkhead transcription factors and MTP, and that inhibition of apoAIV expression might reduce plasma Lipids.
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An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and Lipid Absorption
Journal of Lipid Research, 2010Co-Authors: Jahangir Iqbal, Benny Hung-junn Chang, Streamson C. Chua, Lawrence Chan, Xiaosong Li, Gary J Schwartz, M. Mahmood HussainAbstract:Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and Lipid Absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and Lipid Absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal Lipid Absorption.
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Intestinal Lipid Absorption
American journal of physiology. Endocrinology and metabolism, 2009Co-Authors: Jahangir Iqbal, M. Mahmood HussainAbstract:Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which Lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as protein-independent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of Lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral Lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phosphoLipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol Absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.
Lili Ding - One of the best experts on this subject based on the ideXlab platform.
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Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and Lipid Absorption in mice
Proceedings of the National Academy of Sciences, 2021Co-Authors: Lili Ding, Eryun Zhang, Qiaoling Yang, Lihua Jin, Kyle M. Sousa, Bingning Dong, Yangmeng Wang, Jingyan TianAbstract:Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (Fxr) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific Fxr knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (Bsep) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat Absorption. These findings were verified in sterol 27-hydroxylase (Cyp27a1) knockout mice, which exhibited low intestinal BAs and fat Absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and Lipid Absorption contribute to the metabolic benefits of VSG.
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1942-P: Vertical Sleeve Gastrectomy Confers Metabolic Improvements by Reducing Intestinal Bile Acids and Lipid Absorption in Mice
Diabetes, 2020Co-Authors: Lili Ding, Jingyan Tian, Wendong HuangAbstract:Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the mechanisms through which changes in BA content and signaling contribute to the metabolic effects of VSG remain poorly understood. Therefore, in this study, we aim to systematically evaluate the roles of FXR in VSG and determine the underlying mechanism by which bile acids mediate the beneficial effects of VSG. Our data demonstrated that both intestine- and liver-specific farnesoid X receptor (Fxr) knockout mice retained VSG effects and VSG did not appear to increase FXR activation in the liver or intestine, indicating that hepatic or intestinal FXR is dispensable for the metabolic improvement of VSG. We further found that VSG altered gut microbiota composition and reduced intestinal BA levels in mice, resulting in lower intestinal fat Absorption and concomitant metabolic improvements similar to those observed in Fxr null mice. We then confirmed these findings in sterol 27-hydroxylase knockout (Cyp27a1-/-) mice, which exhibited low intestinal BAs and fat Absorption, did not experience metabolic improvements after VSG. Our findings reveal that reductions in intestinal BAs and Lipid Absorption may underlie the metabolic benefits of VSG. Disclosure L. Ding: None. J. Tian: None. W. Huang: None. Funding NCIR01CA139158; Schaeffer Foundation (to W.H.); Hench Foundation (to W.H.); National Natural Science Foundation of China (81773961); Shanghai Pujiang Program (17PJ1408800 to L.D.)