Deficiency in reverse cholesterol transport in mice augments sepsis

ABSTRACTBackgroundSepsis claims over 215,000 lives and costs $16.7 billion per year in America alone. Recent studies revealed that HDL receptor scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. Using Scarb1I179N mice, a mutant SR-BI mouse model with 90% depletion in hepatic SR-BI, we previously reported that the mutant mice are susceptible to cecal ligation and puncture (CLP)-induced sepsis. However, using a hypo-AlbCreSR-BIfl/fl mouse model, Huby’s group showed that the liver-specific SR-BI KO mice are not more susceptible to CLP-induced sepsis. In this study, we generated a new floxed SR-BI mouse model to clarify the contribution of hepatic SR-BI in sepsis. SR-BI is known as a receptor that plays a key role in reverse cholesterol transport (RCT) by uptaking cholesterol to the liver. So, our established AlbCreSR-BIfl/fl mice (liver-specific SR-BI KO) is an RCT deficiency mice model that can be used to understand the mechanisms of RCT protecting against sepsis and may provide new insight into the pathogenesis of sepsis.Methods and ResultsWe generated SR-BIfl/fl mice by flanking exon 2. We bred the floxed mice with AlbCre mice to generate AlbCreSR-BIfl/fl mice (liver-specific SR-BI KO mice), then the mice were backcrossed to C57BL/6J for 10 generations. As shown in Fig 1, the liver SR-BI expression was normal in SR-BIfl/fl mice as compared to C57BL/6J (B6) mice, but completely depleted in AlbCreSR-BIfl/fl mice. Using this liver-specific SR-BI KO model, we observed that a deficiency in RCT rendered the mice highly susceptible to CLP-induced sepsis as shown by 80% and 14.3% survival of SR-BIfl/fl and AlbCreSR-BIfl/fl mice, respectively. We found aggravated inflammatory cytokine production, altered leukocyte recruitment and slightly increased in the blood and peritoneal bacteria. Moreover, we found RCT deficiency mice increased both free and total cholesterol levels in serum and showed severer hemolysis in AlbCreSR-BIfl/fl mice than SR-BIfl/fl mice during CLP-induced sepsis. Importantly, when we fed AlbCreSR-BIfl/fl mice with probucol to decrease the cholesterol level in serum before performing CLP, the survival rate of AlbCreSR-BIfl/fl mice improved to 88.9%.ConclusionsDeficiency RCT resulting in abnormal metabolism of cholesterol and lipid metabolism is a risk factor in sepsis and maintain normal metabolism of cholesterol may provide a new insight for sepsis therapies.

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Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives

Cardiovascular Therapeutics ◽

10.1155/2022/4610834 ◽

2022 ◽

Vol 2022 ◽

pp. 1-9

Author(s):

Xiuting Xu ◽

Zikai Song ◽

Bao Mao ◽

Guoliang Xu

Keyword(s):

Reverse Cholesterol Transport ◽

Scavenger Receptor ◽

Cholesterol Acyltransferase ◽

Density Lipoprotein ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

The Body ◽

Apolipoprotein A1 ◽

Cholesterol Transport ◽

Class B

Hyperlipidemia characterized by abnormal deposition of cholesterol in arteries can cause atherosclerosis and coronary artery occlusion, leading to atherosclerotic coronary heart disease. The body prevents atherosclerosis by reverse cholesterol transport to mobilize and excrete cholesterol and other lipids. Apolipoprotein A1, the major component of high-density lipoprotein, plays a key role in reverse cholesterol transport. Here, we reviewed the role of apolipoprotein A1-targeting molecules in antiatherosclerosis therapy, in particular ATP-binding cassette transporter A1, lecithin-cholesterol acyltransferase, and scavenger receptor class B type 1.

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Macrophage-to-feces reverse cholesterol transport is impaired in a mouse model of diabetes

Atherosclerosis ◽

10.1016/j.atherosclerosis.2014.05.532 ◽

2014 ◽

Vol 235 (2) ◽

pp. e182-e183

Author(s):

T.L. Errico ◽

X. Chen ◽

D. Santos ◽

H. Quesada-Vázquez ◽

J.M. Martín-Campos ◽

...

Keyword(s):

Mouse Model ◽

Reverse Cholesterol Transport ◽

Cholesterol Transport

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Modulation of Reverse Cholesterol Transport by Lycopene Is Associated with Its Protective Role Against Cigarette Smoke Induced COPD and Lung Carcinogenesis in Ferrets (OR05-02-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz029.or05-02-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Jelena Mustra Rakic ◽

Chun Liu ◽

Sudipta Veeramachaneni ◽

Dayong Wu ◽

Ligi Paul ◽

...

Keyword(s):

Total Cholesterol ◽

Cigarette Smoke ◽

Reverse Cholesterol Transport ◽

Protective Role ◽

Cholesterol Transport ◽

Lung Carcinogenesis ◽

Preneoplastic Lesions ◽

Peripheral Tissues ◽

Lung Lesions ◽

Tobacco Carcinogen

Abstract Objectives Reverse cholesterol transport (RCT), which mediates removal of excess cholesterol from peripheral tissues, is a key player in persistent lung inflammation, a common feature of chronic obstructive pulmonary disease (COPD) and lung cancer, after cigarette smoke (CS) exposure. We have previously shown that lycopene, a carotenoid naturally occurring in tomatoes and tomato products, inhibits tobacco carcinogen (NNK)/CS-induced COPD and preneoplastic lesions in lung of ferrets, but the mechanism is unknown. We hypothesize that the protective role of lycopene against NNK/CS-induced COPD and lung preneoplastic lesions is associated with restoring the RCT in ferrets. Methods Male ferrets (4 groups, n = 12−16/group) were exposed to combination of NNK and CS with or without lycopene feeding at low (LL) and high (HL) doses (equivalent to ∼30 mg and ∼90 mg lycopene/day in humans, respectively) for 22 weeks. Ferrets in NNK/CS groups were given NNK (50 mg/kg body weight, i.p. injection) once a month for 4 consecutive months, and were exposed to CS for 30 min/day for 22 weeks. The animals were fed lycopene or placebo starting three weeks prior to the NNK injections and continued until the end of the study. Results NNK/CS exposure significantly increased total cholesterol levels in both plasma and lungs of ferrets (P < 0.05), which was associated with COPD and lung preneoplastic lesion development. In lungs, HL and LL doses lowered NNK/CS-induced total cholesterol, with HL dose reaching significance (P < 0.05); this was accompanied with the decreased lung lesions. HL group had significantly higher mRNA expression of critical genes involved in RCT (LXRα, PPARα, ABCA1 and ABCG1) as compared to NNK/CS group (P < 0.05). Additionally, HL feeding significantly increased protein levels of both nuclear hormone receptors, LXRα and PPARα, known regulators of ABCA1/G1 transporters (P < 0.05). In plasma, lycopene restored total cholesterol and HDL-C concentrations to normal. Plasma triglyceride, LDL-C and VLDL-C concentrations were not significantly different between groups. Conclusions These data demonstrate an important association between lycopene protection against NNK/CS induced lung lesions and pulmonary cholesterol homeostasis through the restoration of the impaired RCT. Funding Sources NIH/NCI, USDA/ARS grants.

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Gut microbial fatty acid metabolites (KetoA and KetoC) affect the progression of nonalcoholic steatohepatitis and reverse cholesterol transport metabolism in mouse model

Lipids ◽

10.1002/lipd.12219 ◽

2020 ◽

Vol 55 (2) ◽

pp. 151-162 ◽

Cited By ~ 2

Author(s):

Neng Tanty Sofyana ◽

Jiawen Zheng ◽

Yuki Manabe ◽

Yuta Yamamoto ◽

Shigenobu Kishino ◽

...

Keyword(s):

Fatty Acid ◽

Mouse Model ◽

Nonalcoholic Steatohepatitis ◽

Reverse Cholesterol Transport ◽

Cholesterol Transport ◽

Acid Metabolites ◽

Microbial Fatty Acid ◽

Fatty Acid Metabolites

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Effects of Astaxanthin on Reverse Cholesterol Transport and Atherosclerosis in Mice

BioMed Research International ◽

10.1155/2017/4625932 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Tang-Bin Zou ◽

Shan-Shan Zhu ◽

Fei Luo ◽

Wei-Qiao Li ◽

Xue-Rong Sun ◽

...

Keyword(s):

Reverse Cholesterol Transport ◽

Scavenger Receptor ◽

Hdl Cholesterol ◽

High Plasma ◽

Cholesterol Transport ◽

Atp Binding ◽

Type I ◽

Aortic Sinus ◽

Atp Binding Cassette Transporter ◽

Atp Binding Cassette

High plasma level of HDL-cholesterol (HDL-C) has been consistently associated with a decreased risk of atherosclerosis (AS); thus, HDL-C is considered to be an antiatherogenic lipoprotein. The development of novel therapies to enhance the atheroprotective properties of HDL may have the possibility of further reducing the residual AS risk. Reverse cholesterol transport (RCT) is believed to be a primary atheroprotective activity of HDL, which has been shown to promote the efflux of excess cholesterol from macrophage-derived foam cells via ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) and then transport it back to the liver for excretion into bile and eventually into the feces. In the current study, we investigated the effects of astaxanthin on RCT and AS progression in mice. The results showed that short- and long-term supplementation of astaxanthin promote RCT in C57BL/6J and ApoE−/−mice, respectively. Moreover, astaxanthin can relieve the plaque area of the aortic sinus and aortic cholesterol in mice. These findings suggest that astaxanthin is beneficial for boosting RCT and preventing the development of AS.

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Chitosan oligosaccharides promote reverse cholesterol transport and expression of scavenger receptor BI and CYP7A1 in mice

Experimental Biology and Medicine ◽

10.1258/ebm.2011.011275 ◽

2012 ◽

Vol 237 (2) ◽

pp. 194-200 ◽

Cited By ~ 18

Author(s):

Chuanlong Zong ◽

Yang Yu ◽

Guohua Song ◽

Tian Luo ◽

Luqin Li ◽

...

Keyword(s):

Reverse Cholesterol Transport ◽

Scavenger Receptor ◽

Cholesterol Transport ◽

Scavenger Receptor Bi ◽

Chitosan Oligosaccharides

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HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility

Biology of Reproduction ◽

10.1093/biolre/ioab035 ◽

2021 ◽

Author(s):

Naomi C Bernecic ◽

Simon P Graaf ◽

Tamara Leahy ◽

Bart M Gadella

Keyword(s):

Reverse Cholesterol Transport ◽

Cholesterol Efflux ◽

Scavenger Receptor ◽

High Density Lipoproteins ◽

In Vitro Fertilisation ◽

Critical Event ◽

Cholesterol Transport ◽

Type I

ABSTRACT Reverse Cholesterol Transport or cholesterol efflux is part of an extensive plasma membrane remodelling process in spermatozoa that is imperative for fertilisation. For ram spermatozoa, sheep serum is well known to support in vitro fertilisation (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20–40% (as measured by the BODIPY-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8–15)%. Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilisation. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilisation in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF.

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Abstract 147: Hepatic Scavenger Receptor BI Protects Against Polymicrobial-Induced Sepsis Through Promoting LPS Clearance in Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.147 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Ling Guo ◽

Zhong Zheng ◽

Junting Ai ◽

Bin Huang ◽

Xiang-An Li

Keyword(s):

Protective Factor ◽

Adrenal Glands ◽

Cytokine Production ◽

Scavenger Receptor ◽

Cecal Ligation ◽

Protective Role ◽

Bacterial Clearance ◽

Inflammatory Cytokine Production ◽

Scavenger Receptor Bi ◽

Glucocorticoid Production

Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1 I179N mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1 I179N mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1 I179N mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis.

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Abstract 45: Antiatherosclerotic Effects of miR-33 Inhibition: Increased Reverse Cholesterol Transport and Alternative-Activation (M2) of Macrophages

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a45 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Katey J Rayner ◽

Frederick J Sheedy ◽

Christine Esau ◽

Farah N Hussain ◽

Ryan E Temel ◽

...

Keyword(s):

Reverse Cholesterol Transport ◽

Macrophage Polarization ◽

Protective Role ◽

Alternative Activation ◽

Cholesterol Transport ◽

Systemic Delivery ◽

Beneficial Effects ◽

Beneficial Impact ◽

M2 Phenotype

Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL and exploit its atheroprotective effects have remained elusive. Recent studies identified miR-33 as an intronic microRNA, located within the SREBF2 gene, that suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and plasma HDL, suggesting that antagonism of miR-33 may be atheroprotective. We hypothesized that systemic delivery of an oligonucleotide inhibitor of miR-33 would increase plasma HDL and promote reverse cholesterol transport (RCT), and therefore have a beneficial impact on atherosclerosis. To test this, we treated Ldlr -/- mice with established atherosclerotic plaques with anti-miR33 or a control anti-miR for 4 weeks. Treatment with anti-miR-33 increased circulating HDL levels by 37% and enhanced RCT to the plasma, liver, and feces by up to 80%. Consistent with this, anti-miR33-treated mice showed a marked reduction in plaque size and lipid content, as well as an increase in indicators of plaque stability. Laser capture microdissection of lesional CD68+ cells demonstrated that anti-miR33 oligonucleotides directly targeted the plaque macrophages, where they enhanced ABCA1 expression and cholesterol removal. Moreover, macrophages from anti-miR33-treated mice showed an enrichment in anti-inflammatory M2 markers (Arg1, Il10) and reduced expression of proinflammatory M1 markers (iNos and Tnfa). Notably, overexpression of miR-33 in pMφ in vitro decreases markers of the M2 phenotype, Arg1 and Il-4, and increases the expression of inflammatory cytokines such as Tnfa and Il-1b. In contrast, anti-miR-33 polarizes pMφ to an M2 phenotype (Arg1, Fizz1, Il-10 and Il-4), with an associated downregulation of inflammatory genes (Tnfa, Il-1b). Overall, these results indicate that anti-miR33 has multiple beneficial effects on atherosclerosis, including increasing HDL and RCT, and reducing lesional inflammation by promoting macrophage polarization to the reparative M2 state, highlighting the promise for anti-miR33 therapy for the treatment of cardiovascular disease.

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