New Insights Into How the Intestine Can Regulate Lipid Homeostasis and Impact Vascular Disease: Frontiers for New Pharmaceutical Therapies to Lower Cardiovascular Disease Risk

Warnakula, Samantha; Hsieh, Joanne; Adeli, Khosrow; Hussain, M. Mahmood; Tso, Patrick; Proctor, Spencer D.

doi:10.1016/j.cjca.2010.12.020

Cited by 21 publications

(18 citation statements)

References 82 publications

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“…Under normal feeding conditions, lipids that are digested from dietary food are absorbed by enterocytes (ECs) and resynthesized into triglyceride (TG) and packaged into lipoprotein particles that are transported to peripheral tissues for energy supply (Warnakula et al, 2011). Defects in enteric lipid homeostasis have been implicated in obesity, type 2 diabetes, and cardiovascular diseases (Anzai et al, 2009; Warnakula et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Defects in enteric lipid homeostasis have been implicated in obesity, type 2 diabetes, and cardiovascular diseases (Anzai et al, 2009; Warnakula et al, 2011). Thus, characterization of the molecular mechanisms that coordinate lipid uptake, synthesis and mobilization with lipid homeostasis in the intestine is critical for understanding the basis of lipid metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

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Control of Lipid Metabolism by Tachykinin in Drosophila

2014

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Summary The intestine is a key organ for lipid uptake and distribution, and abnormal intestinal lipid metabolism is associated with obesity and hyperlipidemia. Although multiple regulatory gut hormones secreted from enteroendocrine cells (EEs) regulate systemic lipid homeostasis, such as appetite control and energy balance in adipose tissue, their respective roles regarding lipid metabolism in the intestine are not well understood. We demonstrate that Tachykinins (TKs), one of the most abundant secreted peptides expressed in midgut EEs, regulate intestinal lipid production and subsequently control systemic lipid homeostasis in Drosophila, and that TKs repress lipogenesis in enterocytes (ECs) associated with the TKR99D receptor and PKA signaling. Interestingly, nutrient deprivation enhances the production of TKs in the midgut. Finally, unlike the physiological roles of TKs produced from the brain, gut-derived TKs do not affect behavior, thus demonstrating that gut TK hormones specifically regulate intestinal lipid metabolism without affecting neuronal functions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Control of Lipid Metabolism by Tachykinin in Drosophila

2014

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“…Since both liver and intestine can synthesize apoB48 in mice (44), accumulated apoB48 may come from VLDL produced by liver and chylomicrons secreted by intestine. Although fasting plasma samples were analyzed for apoB48 and VLDL production in the current study, it is believed that chylomicrons are continuously secreted by intestine (45). Intestinal NPC1L1 may play an important role in maintaining continuous production of chylomicrons in the fasting state in addition to mediating chylomicron-cholesterol production during postprandial period.…”

Section: Discussionmentioning

confidence: 99%

“…Several major health problems such as insulin resistance, diabetes and obesity are associated with increased postprandial production of chylomicrons (46–49). Chylomicron remnants contribute significantly to the risk of atherosclerosis (45). These previous observations together with our current findings suggest that inhibiting intestinal NPC1L1 might be an attractive strategy in reducing atherosclerosis risk factors in subjects with insulin resistance, type 2 diabetes and obesity.…”

Section: Discussionmentioning

confidence: 99%

Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

et al. 2014

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Objective The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. Methods and results We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses human NPC1L1 in gastrointestinal tract only (DKO/L1IntOnly mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that human NPC1L1 was localized at the intestinal brush border membrane of DKO/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1IntOnly mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1IntOnly mice. Conclusion Our findings from DKO/L1IntOnly mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice.

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“…Prolonged and exaggerated postprandial plasma triacylglycerol (TAG) concentrations and hypercholesterolemia are risk factors for cardiovascular disease or metabolic syndrome [1], [2], [3]. This is clearly related to changes in dietary habits leading to overconsumption of lipids, associated to low physical activity.…”

Section: Introductionmentioning

confidence: 99%

Lipidomic and Spatio-Temporal Imaging of Fat by Mass Spectrometry in Mice Duodenum during Lipid Digestion

et al. 2013

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Intestinal absorption of dietary fat is a complex process mediated by enterocytes leading to lipid assembly and secretion of circulating lipoproteins as chylomicrons, vLDL and intestinal HDL (iHDL). Understanding lipid digestion is of importance knowing the correlation between excessive fat absorption and atherosclerosis. By using time-of-flight secondary ion mass spectrometry (TOF-SIMS), we illustrated a spatio-temporal localization of fat in mice duodenum, at different times of digestion after a lipid gavage, for the first time. Fatty acids progressively increased in enterocytes as well as taurocholic acid, secreted by bile and engaged in the entero-hepatic re-absorption cycle. Cytosolic lipid droplets (CLD) from enterocytes were originally purified separating chylomicron-like, intermediate droplets and smaller HDL-like. A lipidomic quantification revealed their contents in triglycerides, free and esterified cholesterol, phosphatidylcholine, sphingomyelin and ceramides but also in free fatty acids, mono- and di-acylglycerols. An acyl-transferase activity was identified and the enzyme monoacylglycerol acyl transferase 2 (MGAT2) was immunodetected in all CLD. The largest droplets was also shown to contain the microsomal triglyceride transfer protein (MTTP), the acyl-coenzyme A-cholesterol acyltransferases (ACAT) 1 and 2, hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). This highlights the fact that during the digestion of fats, enterocyte CLD contain some enzymes involved in the different stages of the metabolism of diet fatty acids and cholesterol, in anticipation of the crucial work of endoplasmic reticulum in the process. The data further underlines the dual role of chylomicrons and iHDL in fat digestion which should help to efficiently complement lipid-lowering therapy.

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New Insights Into How the Intestine Can Regulate Lipid Homeostasis and Impact Vascular Disease: Frontiers for New Pharmaceutical Therapies to Lower Cardiovascular Disease Risk

Cited by 21 publications

References 82 publications

Control of Lipid Metabolism by Tachykinin in Drosophila

Control of Lipid Metabolism by Tachykinin in Drosophila

Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

Lipidomic and Spatio-Temporal Imaging of Fat by Mass Spectrometry in Mice Duodenum during Lipid Digestion

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