Aim
Perinatal hypercholesterolemia exacerbates the development of atherosclerotic plaques in adult offspring. Here, we aimed to study the effect of maternal treatment with cholestyramine, a ...lipid‐lowering drug, on atherosclerosis development in adult offspring of hypercholesterolemic ApoE‐deficient (ApoE−/−) mice.
Methods
ApoE−/− mice were treated with 3% cholestyramine (CTY) during gestation (G). After weaning, offspring (CTY‐G) were fed control diet until sacrificed at 25weeks of age. Atherosclerosis development in the aortic root of offspring was assessed after oil‐red‐o staining, along with some of predefined atherosclerosis regulators such as LDL and HDL by high‐performance liquid chromatography (HPLC), and bile acids (BA) and trimethylamine N‐oxide (TMAO) by liquid chromatography‐mass spectrometry (LC–MS/MS).
Results
In pregnant dams, cholestyramine treatment resulted in significantly lower plasma total‐ and LDL‐cholesterol as well as gallbladder total BA levels. In offspring, both males and females born to treated dams displayed reduced atherosclerotic plaques areas along with less lipid deposition in the aortic root. No significant change in plasma total cholesterol or triglycerides was measured in offspring, but CTY‐G males had increased HDL‐cholesterol and decreased apolipoproteins B100 to A‐I ratio. This latter group also showed reduced gallbladder total and specifically tauro‐conjugated bile acid pools, whereas for CTY‐G females, hydrophilic plasma tauro‐conjugated BA pool was significantly higher. They also benefited from lower plasma TMAO.
Conclusion
Prenatal cholestyramine treatment reduces atherosclerosis development in adult offspring of ApoE−/− mice along with modulating the plaques' composition as well as some related biomarkers such as HDL‐C, bile acids and TMAO.
Clinical aspects of PCSK9 Cariou, Bertrand; Le May, Cédric; Costet, Philippe
Atherosclerosis,
06/2011, Letnik:
216, Številka:
2
Journal Article
Recenzirano
Abstract Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulating protein that impairs LDL clearance by promoting the LDL receptor (LDLR) degradation. PCSK9 has emerged as a new ...pharmacological target for hypercholesterolemia, and different PCSK9 inhibitors are now evaluated in clinical trials. Here, we propose an overview of the clinical perspectives of PCSK9. First, we describe the clinical features of patients with PCSK9 mutations, and how these variations impact the cardiovascular risk. Then, we extensively discuss the potential role of circulating PCSK9 as a new biomarker of lipid metabolism. Indeed, many studies conducted in healthy and type 2 diabetic patients have tested the association of circulating PCSK9 with LDL-cholesterol as well as with multiple metabolic parameters. The overall picture of the clinical relevance of circulating PCSK9 is complicated by the effect of nutritional status and hypolipidemic drugs such as statins, fibrates, ezetimibe on plasma PCSK9 concentrations. Finally, we present a brief overview of the available therapeutic strategies to inhibit PCSK9.
Elevated plasma triglyceride (TG) levels are an independent risk factor for cardiovascular disease (CVD). Proprotein convertase subtilisin-kexin 9 (PCSK9) – a protein therapeutically targeted to ...lower plasma cholesterol levels – might regulate plasma TG-rich lipoprotein (TRL) levels. We provide a timely and critical review of the current evidence for a role of PCSK9 in TRL metabolism by assessing the impact of PCSK9 gene variants, by reviewing recent clinical data with PCSK9 inhibitors, and by describing the potential mechanisms by which PCSK9 might regulate TRL metabolism. We conclude that the impact of PCSK9 on TRL metabolism is relatively modest, especially compared to its impact on cholesterol metabolism.
PCSK9 modulates triglyceride-rich lipoprotein (TRL) metabolism, but this impact is modest compared to the impact of PCSK9 on cholesterol metabolism.
Plasma proprotein convertase PCSK9 levels are positively associated with plasma TG levels, particularly intermediate-density lipoproteins (IDLs).
Specific, but not all, PCSK9 gain-of-function and loss-of-function variants impact on TRL metabolism.
Studies in mice suggest that PCSK9 impacts on APOB100 secretion during fasting through a low-density lipoprotein receptor (LDLR)-dependent and an LDLR-independent mechanism.
PCSK9 monoclonal antibodies modestly reduce plasma TG levels, mainly by enhancing LDLR-mediated catabolism of IDLs.
Extracellular and intracellular PCSK9 might act in a complementary fashion to regulate TRL metabolism: extracellular PCSK9 by regulating LDLR-mediated catabolism of TRLs, and intracellular PCSK9 by modulating APOB secretion through a so far ill-defined mechanism.
Role of PCSK9 beyond liver involvement Cariou, Bertrand; Si-Tayeb, Karim; Le May, Cédric
Current opinion in lipidology,
06/2015, Letnik:
26, Številka:
3
Journal Article
Recenzirano
Proprotein convertase subtilisin kexin type 9 (PCSK9) acts as an endogenous natural inhibitor of the LDL receptor pathway, by targeting the receptor to lysosomes for degradation. Beside the liver, ...PCSK9 is also expressed at significant levels in other tissues, where its function remains unclear. The current review focuses on the extrahepatic actions of PCSK9.
The generation of liver-specific PCSK9 knockout mice has clearly indicated that PCSK9 affects cholesterol homeostasis via its action on extrahepatic organs. PCSK9 is highly expressed in the intestine, where it controls the production of triglyceride-rich lipoproteins and the transintestinal cholesterol excretion. The role of PCSK9 in the endocrine pancreas and glucose homeostasis remains unclear because conflicting data exist concerning the metabolic phenotype of PCSK9-deficient mice. Sparse data suggest that PCSK9 might also play a role in kidneys, vascular smooth muscle cells, and neurons.
Based on the virtuous combination of genetic and pharmacological approaches, the major function of PCSK9 as a key regulator of hepatic LDL receptor metabolism had quickly emerged. Accumulating evidence indicates that intestinal PCSK9 is also involved in the modulation of lipid homeostasis. Additional studies are warranted to decipher the physiological function of PCSK9 in other extrahepatic tissues and thus to better assess the safety of PCSK9 inhibitors.
OBJECTIVE—Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE.
APPROACH AND RESULTS—We studied ...TICE ex vivo in mouse and human intestinal explants, and in vivo after bile diversion and intestinal cannulation in mice. We provide the first evidence that both low-density lipoprotein (LDL) and high-density lipoprotein deliver cholesterol for TICE in human and mouse jejunal explants at the basolateral side. Proprotein convertase subtilisin kexin type 9 (PCSK9) mice and intestinal explants show increased LDL-TICE, and acute injection of PCSK9 decreases TICE in vivo, suggesting that PCSK9 is a repressor of TICE. The acute repression was dependent on the LDL receptor (LDLR). Further, TICE was increased when mice were treated with Lovastatin. These data point to an important role for LDLR in TICE. However, LDLR mice showed increased intestinal LDL uptake, contrary to what is observed in the liver, and tended to have higher TICE. We interpret these data to suggest that there might be at least 2 mechanisms contributing to TICE; 1 involving LDL receptors and other unidentified mechanisms. Acute modulation of LDLR affects TICE, but chronic deficiency is compensated for most likely by the upregulation of the unknown mechanisms. Using mice deficient for apical multidrug active transporter ATP-binding cassette transporter B1 a and b, and its inhibitor, we show that these apical transporters contribute significantly to TICE.
CONCLUSIONS—TICE is operative in human jejunal explants. It is a metabolically active process that can be acutely regulated, inversely related to cholesterolemia, and pharmacologically activated by statins.
ABSTRACT
Efficient intestinal absorption of dietary vitamin D is required in most people to ensure an adequate status. Thus, we investigated the involvement of ATP binding cassette subfamily B member ...1 (ABCB1) in vitamin D intestinal efflux. Both cholecalciferol (D3) and 25‐hydroxycholecalciferol 25(OH)D3 apical effluxes were decreased by chemical inhibition of ABCB1 in Caco‐2 cells and increased by ABCB1 overexpression in Griptites or Madin‐Darby canine kidney type II cells. Mice deficient for the 2 murine ABCB1s encoded by Abcb1a and Abcb1b genes (Abcb1−/−) displayed an accumulation of 25(OH)D3 in plasma, intestine, brain, liver, and kidneys, together with an increased D3 postprandial response after gavage compared with controls. 25(OH)D3 efflux through Abcb1−/− intestinal expiants was markedly decreased compared with controls. This reduction of 25(OH)D3 transfer from plasma to lumen was further confirmed in vivo in intestine‐perfused mice. Docking experiments established that both D3 and 25(OH)D3 could bind with high affinity to Caenorhabditis elegans P‐glycoprotein, used as an ABCB1 model. Finally, in a group of 39 healthy male adults, a single‐nucleotide polymorphism (SNP) in ABCB1 (rs17064) was significantly associated with the fasting plasma 25(OH)D3 concentration. Thus, we showed here for the first time that ABCB1 is involved in neo‐absorbed vitamin D efflux by the enterocytes and that it also contributes to vitamin D transintestinal excretion and likely impacts vitamin D status.—Margier, M., Collet, X., leMay, C., Desmarchelier, C., André, F., Lebrun, C., Defoort, C., Bluteau, A., Borel, P., Lespine, A., Reboul, E. ABCB1 (P‐glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux. FASEB J. 33, 2084–2094 (2019). www.fasebj.org
Patients with type 2 diabetes mellitus (T2DM) represent a high-risk population for both cardiovascular diseases and severe coronavirus disease 2019 (COVID-19). Recent studies have reported ...interactions between statin treatment and COVID-19-related outcomes. The study reported here specifically assessed the association between routine statin use and COVID-19-related outcomes in inpatients with T2DM.
The Coronavirus–SARS-CoV-2 and Diabetes Outcomes (CORONADO) study was a nationwide observational study aiming to describe the phenotypic characteristics and prognosis of T2DM patients with COVID-19 admitted to 68 French hospitals between 10 March and 10 April 2020. The composite primary outcome comprised tracheal intubation and/or death within 7 and 28 days of admission. The association between statin use and outcomes was estimated by logistic regression analysis after applying inverse probability of treatment weighting (IPTW) using a propensity score-weighting approach.
Of the 2449 patients with T2DM (881 women, 1568 men; aged 70.9 ± 12.5 years) suitable for analysis, 1192 (49%) were using statin treatment before admission. In unadjusted analyses, patients using statins had rates of the primary outcome similar to those of non-users within both 7 (29.8% vs 27.0%, respectively; P = 0.1338) and 28 days (36.2% vs 33.8%, respectively; P = 0.2191) of admission. However, mortality rates were significantly higher in statin users within 7 (12.8% vs 9.8%, respectively; P = 0.02) and 28 days (23.9% vs 18.2%, respectively; P < 0.001). After applying IPTW, significant associations were observed with statin use and the primary outcome within 7 days (OR 95% CI: 1.38 1.04–1.83) and with death within both 7 (OR 95% CI: 1.74 1.13–2.65) and 28 days (OR 95% CI: 1.46 1.08–1.95).
Routine statin treatment is significantly associated with increased mortality in T2DM patients hospitalized for COVID-19.
•We explored the involvement of ABCB1 in vitamin K efflux.•Inhibition of ABCB1 in Caco-2 cells decreased vitamin K efflux.•ABCB1 overexpression in Griptite cells increased vitamin K efflux.•Vitamin K ...postprandial response was higher in male Abcb1−/− mice compared to WT mice.
ABCB1 (P-glycoprotein/MDR1) is a multidrug efflux transporter that has previously been involved in cholesterol and vitamin D metabolism. Our aim was to explore whether ABCB1 is also involved in vitamin K efflux. Vitamin K apical efflux was significantly decreased in presence of ABCB1 inhibitor in Caco-2 cells (−20.4%; p < 0.05) and increased in Griptite cells overexpressing ABCB1 (+40.7%; p < 0.05). In vivo, the vitamin K postprandial response was higher in male Abcb1−/− mice after gavage compared to control animals (+115%; p < 0.05), but was unchanged in female mice. Finally, a vitamin K transintestinal efflux and a biliary vitamin K efflux were observed, but the specific involvement of ABCB1 could not be confirmed in these pathways. Overall, we showed for the first time that ABCB1 is involved in enterocyte vitamin K efflux in both cell and mouse models and regulates vitamin K absorption in mice.
Scope
Most people are vitamin D insufficient around the world. Vitamin D intestinal absorption should thus be optimized. The role of the ATP‐binging cassette G5/G8 (ABCG5/G8) heterodimer in vitamin D ...intestinal efflux is investigated.
Methods and Results
Both cholecalciferol and 25‐hydroxycholecalciferol apical effluxes are increased by ABCG5/G8 overexpression in human Griptite cells. Mice deficient in ABCG5/G8 at the intestinal level (I‐Abcg5/g8−/− mice) display an accumulation of cholecalciferol in plasma in females and in liver in males compared to control animals. I‐Abcg5/g8−/− mice display a delay in cholecalciferol postprandial response after gavage compared with controls. 25‐Hydroxycholecalciferol transfer from plasma to lumen is observed in vivo in intestine‐perfused mice, and the lack of intestinal ABCG5/G8 complex induces a decrease in this efflux, while vitamin D bile excretion remains unchanged.
Conclusion
Overall, it is showed for the first time that the ABCG5/G8 heterodimer regulates the kinetics of absorption of dietary vitamin D by contributing to its efflux back to the lumen, and that it also participates in vitamin D transintestinal efflux.
Cholecalciferol and 25‐hydroxycholecalciferol apical effluxes are increased in human cells overexpressing ABCG5/G8. ABCG5/G8 inactivation in mouse intestine induces an accumulation of cholecalciferol in plasma or liver, a delay in cholecalciferol postprandial response, and a decrease in 25‐hydroxycholecalciferol transfer from plasma to lumen. ABCG5/G8 thus regulates vitamin D absorption kinetics by contributing to its efflux back to the lumen and participates in vitamin D transintestinal efflux.
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