Immunological Quantitation and Localization of ACAT-1 and ACAT-2 in Human Liver and Small Intestine

Chang, Catherine C.Y.; Sakashita, Naomi; Ørnvold, Kim; Lee, Oneil; Chang, Ellen T.; Dong, Ruhong; Song, Lin; Lee, Chi‐Yu Gregory; Strom, Stephen C.; Kashyap, Randeep; Fung, John J.; Farese, Robert V.; Patoiseau, Jean-François; Delhon, A.; Chang, Ta Yuan

doi:10.1074/jbc.m003927200

Cited by 202 publications

(58 citation statements)

References 45 publications

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“…A final aspect we considered for the therapeutic application of ACAT inhibitors in HBV and HBV-related HCC was whether they could exert any direct effect on HBV replication independent of the immune response. ACAT is highly expressed in hepatocytes 42 and cholesteryl ester is one of the components of HBsAg 43 . We, therefore, hypothesised that inhibiting cholesterol esterification in infected hepatocytes may interfere with the formation of new HBsAg-containing virions and subviral particles.…”

Section: Resultsmentioning

confidence: 99%

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%

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

et al. 2021

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“…The incorporation of [ 14 C]oleic acid or [ 14 C]acetic acid into cellular lipids was carried out over 5 h, either immediately after flavonoid addition or after a 19-h preincubation with the flavonoids. As shown in Table 2, without a 19-h preincubation, the incorporation of [ 14 C]oleic acid into CE was reduced by 37% (P Ͻ 0.05) and 70% (P Ͻ 0.001) at 50 sis was decreased by naringenin (42% at 200 M, P Ͻ 0.05) and hesperetin (38% at 200 M, P Ͻ 0.05).…”

Section: Cellular Lipid Biosynthesis Acat Activities and Ce Hydrolysismentioning

confidence: 86%

Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP

Wilcox¹,

Borradaile²,

Dreu

et al. 2001

Journal of Lipid Research

217

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The citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. The ability of these flavonoids to modulate apolipoprotein B (apoB) secretion and cellular cholesterol homeostasis was determined in the human hepatoma cell line, HepG2. apoB accumulation in the media decreased in a dose-dependent manner following 24-h incubations with naringenin (up to 82%, P Ͻ 0.00001) or hesperetin (up to 74%, P Ͻ 0.002). Decreased apoB secretion was associated with reduced cellular cholesteryl ester mass. Cholesterol esterification was decreased, dose-dependently, up to 84% ( P Ͻ 0.0001) at flavonoid concentrations of 200 M. Neither flavonoid demonstrated selective inhibition of either form of acyl CoA:cholesterol acyltransferase (ACAT) as determined using CHO cells stably transfected with either ACAT1 or ACAT2. However, in HepG2 cells, ACAT2 mRNA was selectively decreased ( ؊ 50%, P Ͻ 0.001) by both flavonoids, whereas ACAT1 mRNA was unaffected. In addition, naringenin and hesperetin decreased both the activity ( ؊ 20% to ؊ 40%, P Ͻ 0.00004) and expression ( ؊ 30% to ؊ 40%, P Ͻ 0.02) of microsomal triglyceride transfer protein (MTP). Both flavonoids caused a 5-to 7-fold increase ( P Ͻ 0.02) in low density lipoprotein (LDL) receptor mRNA, which resulted in a 1.5-to 2-fold increase in uptake and degradation of 125 I-LDL.We conclude that both naringenin and hesperetin decrease the availability of lipids for assembly of apoB-containing lipoproteins, an effect mediated by 1) reduced activities of ACAT1 and ACAT2, 2) a selective decrease in ACAT2 expression, and 3) reduced MTP activity. Together with an enhanced expression of the LDL receptor, these mechanisms may explain the hypocholesterolemic properties of the citrus flavonoids. -Wilcox, L. J., N. M. Borradaile, L. E. de Dreu, and M. W. Huff. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP.

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“…Two ACAT isoenzymes have been identified in mammals so far, consistent with their different tissue distribution. ACAT1 is widely expressed throughout the body, suggesting its involvement in maintaining cholesterol homeostasis, while ACAT2 expression is exclusive in enterocytes and hepatocytes, where it contributes to lipoprotein biosynthesis and assembly ( 68 , 69 ).…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

et al. 2021

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Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

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Immunological Quantitation and Localization of ACAT-1 and ACAT-2 in Human Liver and Small Intestine

Cited by 202 publications

References 45 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

Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

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