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Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1fl/fl) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1fl/fl mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.

Key Points The association of low plasma high-density lipoprotein cholesterol (HDL-C) concentration with elevated cardiovascular disease risk is firmly established in men and women over a wide age range, across several cardiometabolic disease states, including type 2 diabetes, and in many populations and ethnic groups. These associations underpinned the HDL hypothesis coined 40 years ago, stating that “a reduction of plasma HDL concentration may accelerate the development of atherosclerosis, and hence ischaemic heart disease, by impairing the clearance of cholesterol from the arterial wall”. Although the hypothesis was about HDL particle concentration, the evidence for the idea was based on HDL-C concentration data, as there was no method of measuring the former at the time. Genetic studies, including Mendelian randomization analysis, have shown that plasma HDL-C itself is not anti-atherogenic. However, genetic epidemiology has not yet been used to test the causality of low HDL particle number and coronary heart disease. Two short-term clinical trials of the effects of intravenous reconstituted HDLs on coronary lesions in patients with acute coronary syndrome gave encouraging results, but failed to provide unequivocal evidence of benefit. The small molecules tested to date in Phase III outcome trials do not specifically target HDL, and more specifically HDL particle number, and therefore the HDL hypothesis is yet to be tested. Three classes of agents that raise HDL-C in addition to lowering low-density lipoprotein (LDL) and/or plasma triglycerides have been tested. Although trial results with fibrates and niacin produced variable outcomes, meta-analyses supported the beneficial effects of both, although it was not possible to attribute them to HDL. Two trials of cholesteryl ester transfer protein (CETP) inhibitors have failed to show benefit, in one case possibly owing to an increase in blood pressure. The interrelationships between HDL-C concentration, HDL particle number and HDL particle subpopulations of defined composition are complex, as are their relationships to reverse cholesterol transport and other anti-atherogenic properties. Nevertheless, an understanding of these relationships will be essential for the rational development of new HDL therapies. Several novel approaches are under clinical development, including second-generation CETP inhibitors, new HDL infusion therapies, recombinant lecithin–cholesterol acyltransferase (LCAT) infusion therapy, and apolipoprotein A1 (APOA1) transcriptional upregulators. Additional strategies to target HDL metabolism that are emerging include APOA1-mimetic peptides, liver X receptor agonists, farnesoid X receptor agonists, endothelial lipase inhibitors, antagonists of microRNAs and antisense oligonucleotides targeted at the genes that are implicated in HDL metabolism. Evidence supporting the hypothesis that raising plasma levels of high-density lipoprotein (HDL) cholesterol could be cardioprotective has fuelled intense efforts to develop HDL-targeted therapies, but several recent clinical trial failures have introduced controversy. Kingwell and colleagues discuss the current understanding of the HDL hypothesis, considering what has been learned, what remains to be tested and how this knowledge could be used in the development of novel therapies. Since the discovery in the 1970s that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular outcome, it has been postulated that HDL is anti-atherogenic and that increasing HDL-C levels is a promising therapeutic strategy. However, the recent failure of three orally active, HDL-C-raising agents has introduced considerable controversy, prompting the question of whether increasing the cholesterol cargo of HDL in a non-selective manner is an effective pharmacological approach for the translation of its atheroprotective and vasculoprotective activities. The interrelationships between HDL-C concentration, HDL particle number and levels of diverse HDL particle subpopulations of defined composition are complex, as are their relationships with reverse cholesterol transport and other anti-atherogenic functions. Such complexity highlights the incompleteness of our understanding of the biology of HDL particles. This article examines the HDL hypothesis in molecular and mechanistic terms, focusing on features that have been addressed, those that remain to be tested, and potential new targets for future pharmacological interventions.

Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78–Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters. Furthermore, ACAT2 knockout mice were more susceptible to high-fat diet-associated insulin resistance. By contrast, expression of a constitutively stable form of ACAT2 (C277A) resulted in higher insulin sensitivity. Together, these data indicate that lipid-induced stabilization of ACAT2 ameliorates lipotoxicity from excessive cholesterol and fatty acid. This unconventional cysteine ubiquitylation of ACAT2 constitutes an important mechanism for sensing lipid-overload-induced ROS and fine-tuning lipid homeostasis. Wang et al. show that lipid-induced ROS lead to ACAT2 stabilization by oxidizing a cysteine residue, thereby preventing its ubiquitylation and ACAT2 degradation. They further show that ACAT2 stabilization improves lipotoxicity and insulin resistance.

As members of the membrane-bound O -acyltransferase (MBOAT) enzyme family, acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyse the transfer of an acyl group from acyl-coenzyme A to cholesterol to generate cholesteryl ester, the primary form in which cholesterol is stored in cells and transported in plasma 1 . ACATs have gained attention as potential drug targets for the treatment of diseases such as atherosclerosis, Alzheimer’s disease and cancer 2 – 7 . Here we present the cryo-electron microscopy structure of human ACAT1 as a dimer of dimers. Each protomer consists of nine transmembrane segments, which enclose a cytosolic tunnel and a transmembrane tunnel that converge at the predicted catalytic site. Evidence from structure-guided mutational analyses suggests that acyl-coenzyme A enters the active site through the cytosolic tunnel, whereas cholesterol may enter from the side through the transmembrane tunnel. This structural and biochemical characterization helps to rationalize the preference of ACAT1 for unsaturated acyl chains, and provides insight into the catalytic mechanism of enzymes within the MBOAT family 8 . The structure of human ACAT1, which catalyses the transfer of an acyl group from acyl-coenzyme A to cholesterol to form cholesteryl ester, is resolved by cryo-electron microscopy.

Immune functions decline with aging, leading to increased susceptibility to various diseases including tumors. Exploring aging-related molecular targets in elderly patients with cancer is thus highly sought after. Here we find that an ER transmembrane enzyme, sterol O-acyltransferase 2 (SOAT2), is overexpressed in regulatory T (Treg) cells from elderly patients with lung squamous cell carcinoma (LSCC), while radiomics analysis of LSCC patients associates increased SOAT2 expression with reduced immune infiltration and poor prognosis. Mechanically, ex vivo human and mouse Treg cell data and in vivo mouse tumor models suggest that SOAT2 overexpression in Treg cells promotes cholesterol metabolism by activating the SREBP2-HMGCR-GGPP pathway, leading to enhanced Treg suppresser functions but reduced CD8 + T cell proliferation, migration, homeostasis and anti-tumor immunity. Our study thus identifies a potential mechanism responsible for altered Treg function in the context of immune aging, and also implicates SOAT2 as a potential target for tumor immunotherapy. Aging-related immune alteration has been attributed to increased susceptibility to infection and cancer. Here the authors show, using both lung cancer samples and mouse models, that aged Treg cells express higher levels of an ER enzyme, SOAT2, have altered cholesterol metabolism, and induce CD8 + T cell senescence to dampen anti-tumor immunity.

Background The association of rs1044925 polymorphism in the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene and serum lipid profiles is not well known in different ethnic groups. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was carried out to clarify the association of rs1044925 polymorphism in the ACAT-1 gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 626 subjects of Bai Ku Yao and 624 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of rs1044925 polymorphism in the ACAT-1 gene was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han ( P < 0.01 for all). The frequency of A and C alleles was 79.0% and 21.0% in Bai Ku Yao, and 87.3% and 12.7% in Han ( P < 0.001); respectively. The frequency of AA, AC and CC genotypes was 63.2%, 31.4% and 5.2% in Bai Ku Yao, and 75.6%, 23.2% and 1.1% in Han ( P < 0.001); respectively. The levels of TC, LDL-C and ApoB in Bai Ku Yao but not in Han were different between the AA and AC/CC genotypes in females but not in males ( P < 0.05 for all). The C allele carriers had lower serum TC, LDL-C and ApoB levels as compared with the C allele noncarriers. The levels of TC, LDL-C and ApoB in Bai Ku Yao but not in Han were correlated with genotypes in females but not in males ( P < 0.05 for all). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, and blood pressure in both ethnic groups ( P < 0.05-0.001). Conclusions These results suggest that the polymorphism of rs1044925 in the ACAT-1 gene is mainly associated with female serum TC, LDL-C and ApoB levels in the Bai Ku Yao population. The C allele carriers had lower serum TC, LDL-C and ApoB levels than the C allele noncarriers.

Background Although cholesterol metabolism is a common pathway for the development of antitumor drugs, there are no specific targets and drugs for clinical use. Here, based on our previous study of sterol O-acyltransferase 1 (SOAT1) in hepatocelluar carcinoma, we sought to screen an effective targeted drug for precise treatment of hepatocelluar carcinoma and, from the perspective of cholesterol metabolism, clarify the relationship between cholesterol regulation and tumorigenesis and development. Methods In this study, we developed a virtual screening integrated affinity screening technology for target protein drug screening. A series of in vitro and in vivo experiments were used for drug activity verification. Multi-omics analysis and flow cytometry analysis were used to explore antitumor mechanisms. Comparative analysis of proteome and transcriptome combined with survival follow-up information of patients reveals the clinical therapeutic potential of screened drugs. Results We screened three compounds, nilotinib, ABT-737, and evacetrapib, that exhibited optimal binding with SOAT1. In particular, nilotinib displayed a high affinity for SOAT1 protein and significantly inhibited tumor activity both in vitro and in vivo. Multi-omics analysis and flow cytometry analysis indicated that SOAT1-targeting compounds reprogrammed the cholesterol metabolism in tumors and enhanced CD8 + T cells and neutrophils to suppress tumor growth. Conclusions Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of SOAT1-targeting compounds. Graphical Abstract

Overexpression of acyl-coenzyme A:cholesterol acyltransferase (ACAT) results in increased cholesteryl ester levels and has been involved in a variety of cancer types. As a consequence, cholesterol metabolism has raised interest as a potential target for cancer treatment. Inhibition of ACAT results in suppression of proliferation in a range of cancer cell types both in vitro and in vivo. The exact mechanism of this phenomenon is being investigated, and the most important findings are presented in this review.

Signaling by fibroblast growth factor receptors (FGFRs) is active in up to 85% of breast cancers and results in enhanced proliferation, migration, and invasion of tumor cells. Here, we show that FGFR signaling regulates cholesterol metabolism in breast cancer. Specifically, we demonstrate that FGFR activation promotes cellular cholesterol storage by upregulating expression of the enzyme sterol O-acyltransferase 1 (SOAT1). Moreover, we demonstrate that inhibition of SOAT1 attenuates FGFR-driven colony formation and invasion in tumor cells, which correlates with reduced expression of matrix metalloproteinase expression. Furthermore, genetic knockdown of SOAT1 decreases mammary tumor growth in vivo. Taken together, these findings suggest a largely undiscovered metabolic role for FGFR signaling in regulating cholesterol metabolism in breast cancer and present a therapeutic vulnerability that could be targeted in FGFR-driven cancers.

Aging and apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer’s disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4-dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.