The cholesterol content of normal tissues and the effect of intravenous injections of cholesterol thereon

Chamberlain, E. Noble

doi:10.1113/jphysiol.1928.sp002523

Cited by 16 publications

(7 citation statements)

References 2 publications

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“…1s ) with only one donor failing to show an increase in intrahepatic responses to any HBV peptide pool tested. We postulated that the high local concentrations of cholesterol in the liver 21 , a central hub for lipid metabolism, could contribute to this heightened sensitivity of local responses to ACAT inhibition. In support of this possibility, T cells showed a significantly enhanced proliferative response to ACAT inhibition after incubation in high cholesterol media (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The liver, and many tumours, provide microenvironments that are rich in cholesterol 21 , 23 , 36 , which is required by cells as a major component of lipid bilayers for membrane fluidity 23 . ACAT catalyses the esterification of excess intracellular free cholesterol for storage in neutral lipid droplets, that emerging data reveal can have opposing effects in tumours and immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

et al. 2021

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Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

et al. 2021

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“…It is interesting to find, therefore, that the decrease of blood cholesterol which occurs in pregnant rabbits is accompanied usually by a decrease in suprarenal cholesterol, and the results bear out the frequent statement that blood cholesterol generally runs parallel with suprarenal cholesterol, though, as the writer has shown, by increasing the amount of cholesterol in the blood by intravenous injection the amount in the suprarenal is not increased but even diminished (8).…”

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confidence: 95%

Sex differences in the cholesterol content of tissues1

Chamberlain¹

1929

The Journal of Physiology

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IT has been known for a considerable time that variations in blood cholesterol occur during pregnancy, and it was not entirely unexpected therefore when the sex differences in the cholesterol content of tissues to be described here were demonstrated. These sex differences were discovered during the examination of a large number of normal rabbits (8), when it was desired to have estimations of the cholesterol content of various tissues for purposes of control.Before including both sexes in the series of controls, it was considered advisable to determine whether or not any material differences existed between the two sexes. Experiments soon showed that such differences did exist, and doe rabbits were discarded for control purposes, but the differences noted were deemed worthy of further investigation.The results of this investigation are set forth here, together with the influence of pregnancy on the differences described.Experimental. The aniimals used were rabbits and the tissues examined included suprarenals, ovaries, spleen, kidney, liver and brain. The procedure and method of estimation of cholesterol were similar to those previously used and described (8), but it must be emphasized again that with the method used only gross variations (over 20 p.c.) have been regarded as significant.Results. These may be considered under the headings of the different organs and tissues, and the details are set forth in tabular form.All figures refer to "total cholesterol," i.e. to free and combined cholesterol estimated together. This, admittedly, is not so satisfactory as having separate estimations of the free and ester cholesterol, but nevertheless the results obtained are significant both in themselves and as affording guidance to more detailed study, and the simplicity of the procedure has enabled a much larger number of experiments to be made than would otherwise have been possible.

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“…We have shown increased antiviral activity following treatment of circulating T cells; however immune responses at the site of disease, the lung and upper respiratory tract, are shaped by the local microenvironment and nutrient availability. The lung is enriched in cholesterol compared to blood (Chamberlain, 1928) with cholesterol constituting the main neutral lipid in surfactant (Keating et al, 2007). We previously reported that ACAT inhibition is enhanced in the presence of high cholesterol.…”

Section: Discussionmentioning

confidence: 99%

An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity

Schmidt

Wing

Peters

et al. 2022

Preprint

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The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies have uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 entry and fusion independent of transmembrane protease serine 2 expression in multiple cell types. We also demonstrate a role for ACAT in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled in the acute phase of infection. Thus, re-purposing of available ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.

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The cholesterol content of normal tissues and the effect of intravenous injections of cholesterol thereon

Cited by 16 publications

References 2 publications

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

Sex differences in the cholesterol content of tissues1

An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity

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