RESUMO
HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR-double KO (ALKO), and ALDH2 rs671-knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency-induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Aldeído Desidrogenase , Lipoproteínas HDL , Receptores X do Fígado , Fígado , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Animais , Doenças Cardiovasculares/metabolismo , Humanos , Lipoproteínas HDL/biossíntese , Fígado/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Camundongos , Poli(ADP-Ribose) Polimerase-1 , Ativação TranscricionalRESUMO
HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2) is primarily responsible for detoxifying ethanol-derived acetaldehyde and endogenous lipid aldehydes derived from lipid peroxidation. Epidemiological and Genome Wide Association Studies (GWAS) have linked an inactive ALDH2 rs671 variant, responsible for alcohol flush in nearly 8% world population and 40% of Asians, with cholesterol levels and higher risk of cardiovascular disease (CVD) but the underlying mechanism remains elusive. Here we find that the cholesterol levels in the serum and liver of ALDH2 knockout (AKO) and ALDH2 rs671 knock-in (AKI) mice are significantly increased, consistent with the increase of intermediates in the cholesterol biosynthetic pathways. Mechanistically, mitochondrial ALDH2 translocates to the endoplasmic reticulum to promote the formation of GP78/Insig1/HMGCR complex to increase HMGCR degradation through ubiquitination. Conversely, ALDH2 mutant or ALDH2 deficiency in AKI or AKO mice stabilizes HMGCR, resulting in enhanced cholesterol synthesis, which can be reversed by Lovastatin. Moreover, ALDH2-regulated cholesterol synthesis is linked to the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). Together, our study has identified that ALDH2 is a novel regulator of cholesterol synthesis, which may play an important role in CVD.
Assuntos
Estudo de Associação Genômica Ampla , Fígado , Acil Coenzima A , Aldeído-Desidrogenase Mitocondrial , Aldeído Oxirredutases , Animais , Colesterol , Hidroximetilglutaril-CoA Redutases , CamundongosRESUMO
Cardiovascular disease (CVD), including heart attack, stroke, heart failure, arrhythmia, and other congenital heart diseases remain the leading cause of morbidity and mortality worldwide. The leading cause of deaths in CVD is attributed to myocardial infarction due to the rupture of atherosclerotic plaque. Atherosclerosis refers a condition when restricted or even blockage of blood flow occurs due to the narrowing of blood vessels as a result of the buildup of plaques composed of oxidized lipids. It is well-established that free radical oxidation of polyunsaturated fatty acids (PUFAs) in lipoproteins or cell membranes, termed lipid peroxidation (LPO), plays a significant role in atherosclerosis. LPO products are involved in immune responses and cell deaths in this process, in which previous evidence supports the role of programmed cell death (apoptosis) and necrosis. Ferroptosis is a newly identified form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels, which exhibits distinct features from apoptosis, necrosis and autophagy in morphology, biochemistry and genetics. Emerging evidence appears to demonstrate that ferroptosis is also involved in CVD. In this review, we summarize the recent progress on ferroptosis in CVD and atherosclerosis, highlighting the role of free radical LPO. The evidence underlying the ferroptosis and challenges in the field will also be critically discussed.
Assuntos
Doenças Cardiovasculares/metabolismo , Peróxidos Lipídicos/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/patologia , Ferroptose , Radicais Livres/química , Radicais Livres/metabolismo , Humanos , Peróxidos Lipídicos/químicaRESUMO
Polyunsaturated fatty acids (PUFAs) in the cellular membrane can be oxidized by various enzymes or reactive oxygen species (ROS) to form many oxidized lipids. These metabolites are highly bioactive, participating in a variety of physiological and pathophysiological processes. Mass spectrometry (MS), coupled with Liquid Chromatography, has been increasingly recognized as an indispensable tool for the analysis of oxidized lipids due to its excellent sensitivity and selectivity. We will give an update on the understanding of the molecular mechanisms related to generation of various oxidized lipids and recent progress on the development of LC-MS in the detection of these bioactive lipids derived from fatty acids, cholesterol esters, and phospholipids. The purpose of this review is to provide an overview of the formation mechanisms and technological advances in LC-MS for the study of oxidized lipids in human diseases, and to shed new light on the potential of using oxidized lipids as biomarkers and mechanistic clues of pathogenesis related to lipid metabolism. The key technical problems associated with analysis of oxidized lipids and challenges in the field will also discussed.
Assuntos
Aterosclerose/metabolismo , Ésteres do Colesterol/análise , Colesterol/análise , Ácidos Graxos Insaturados/análise , Lipidômica/métodos , Neoplasias Hepáticas/metabolismo , Animais , Aterosclerose/diagnóstico , Aterosclerose/patologia , Biomarcadores/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Colesterol/química , Colesterol/metabolismo , Ésteres do Colesterol/química , Ésteres do Colesterol/metabolismo , Cromatografia Líquida/instrumentação , Cromatografia Líquida/métodos , Modelos Animais de Doenças , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Humanos , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Lipidômica/instrumentação , Neoplasias Hepáticas/química , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Camundongos , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodosRESUMO
Cardiovascular diseases (CVD), including ischemic heart diseases and cerebrovascular diseases, are the leading causes of morbidity and mortality worldwide. Atherosclerosis is the major underlying factor for most CVD. It is well-established that oxidative stress and inflammation are two major mechanisms leading to atherosclerosis. Under oxidative stress, polyunsaturated fatty acids (PUFA)-containing phospholipids and cholesterol esters in cellular membrane and lipoproteins can be readily oxidized through a free radical-induced lipid peroxidation (LPO) process to form a complex mixture of oxidation products. Overwhelming evidence demonstrates that these oxidized lipids are actively involved in the inflammatory responses in atherosclerosis by interacting with immune cells (such as macrophages) and endothelial cells. In addition to lipid lowering in the prevention and treatment of atherosclerotic CVD, targeting chronic inflammation has been entering the medical realm. Clinical trials are under way to lower the lipoprotein (a) (Lp(a)) and its associated oxidized phospholipids, which will provide clinical evidence that targeting inflammation caused by oxidized lipids is a viable approach for CVD. In this review, we aim to give an update on our understanding of the free radical oxidation of LPO, analytical technique to analyze the oxidation products, especially the oxidized phospholipids and cholesterol esters in low density lipoproteins (LDL), and focusing on the experimental and clinical evidence on the role of lipid oxidation in the inflammatory responses associated with CVD, including myocardial infarction and calcific aortic valve stenosis. The challenges and future directions in understanding the role of LPO in CVD will also be discussed.
Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Aterosclerose/metabolismo , Calcinose/metabolismo , Eicosanoides/metabolismo , Ácidos Graxos Insaturados/metabolismo , Infarto do Miocárdio/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/patologia , Ácidos Araquidônicos/metabolismo , Aterosclerose/diagnóstico , Aterosclerose/patologia , Calcinose/diagnóstico , Calcinose/patologia , Ésteres do Colesterol/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Radicais Livres/metabolismo , Humanos , Inflamação , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Lipoproteína(a)/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/patologia , Estresse Oxidativo , Fosfolipídeos/metabolismoRESUMO
Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme detoxifying acetaldehyde and endogenous lipid aldehydes; previous studies suggest a protective role of ALDH2 against cardiovascular disease (CVD). Around 40% of East Asians carrying the single nucleotide polymorphism (SNP) ALDH2 rs671 have an increased incidence of CVD. However, the role of ALDH2 in CVD beyond alcohol consumption remains poorly defined. Here we report that ALDH2/LDLR double knockout (DKO) mice have decreased atherosclerosis compared with LDLR-KO mice, whereas ALDH2/APOE-DKO mice have increased atherosclerosis, suggesting an unexpected interaction of ALDH2 with LDLR. Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. Interestingly, an interaction of cytosolic LDLR C-terminus with AMPK blocks ALDH2 phosphorylation and subsequent nuclear translocation, whereas ALDH2 rs671 mutant in human macrophages attenuates this interaction, which releases ALDH2 to the nucleus to suppress ATP6V0E2 expression, resulting in increased foam cells due to impaired lysosomal function. Our studies reveal a novel role of ALDH2 and LDLR in atherosclerosis and provide a molecular mechanism by which ALDH2 rs671 SNP increases CVD.
Assuntos
Proteínas Quinases Ativadas por AMP , Aldeído-Desidrogenase Mitocondrial , Aterosclerose , Células Espumosas/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de LDL , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Espumosas/patologia , Humanos , Lisossomos/genética , Lisossomos/metabolismo , Camundongos , Camundongos Knockout para ApoE , Mutação , Fosforilação , Domínios Proteicos , Receptores de LDL/genética , Receptores de LDL/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismoRESUMO
Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD.
Assuntos
Ésteres do Colesterol/metabolismo , Colesterol/metabolismo , Hepatócitos/metabolismo , Macrófagos/metabolismo , Idoso , Animais , Biomarcadores , Doenças Cardiovasculares , Ésteres do Colesterol/genética , Cromatografia Líquida , Modelos Animais de Doenças , Feminino , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/metabolismo , Masculino , Espectrometria de Massas , Metaboloma , Camundongos , Pessoa de Meia-Idade , Receptores de LDL/metabolismoRESUMO
Cholesterol is an important lipid for maintaining cell membrane fluidity and generation of various hormones and bile acids. Thus, it is critical to maintain cholesterol homeostasis including absorption, trafficking, biosynthesis, and efflux; dysregulation of cholesterol homeostasis may lead to human disorders such as atherosclerosis. As a cholesterol sensor, nuclear receptor liver X receptor (LXR) is an important factor regulating cholesterol homeostasis. Extensive research has been carried out to examine the roles of LXR in atherosclerosis. In this review, we summarize our current understanding of the mechanisms how LXR regulates cholesterol synthesis, efflux, absorption, and conversion of cholesterol esters to cholesterol in the context of atherosclerosis. In addition, we also discuss the possibility of targeting LXR and cholesterol homeostasis as a potential interventional strategy for treating atherosclerosis.