ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice.

ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL), and its mutations cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients exhibit cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others previously showed that ABCA1 deficiency causes hyperactivation of the SREBP2 pathway in vitro. Here, we show using Abca1 knockout mice that ABCA1 deficiency leads to tissue-specific dysregulation of SREBP2 activity in a nutritional status-dependent manner, which may underlie the pathophysiology of TD.

Role of ABCA1 in Atherosclerosis: Novel Mutations and Potential Plant-derived Therapies.

ATP-binding cassette transporter A1 (ABCA1) is one of the key proteins regulating cholesterol homeostasis and playing a crucial role in atherosclerosis development. ABCA1 regulates the rate-limiting step of reverse cholesterol transport, facilitates the efflux of surplus intracellular cholesterol and phospholipids, and suppresses inflammation through several signalling pathways. At the same time, many mutations and Single Nucleotide Polymorphisms (SNPs) have been identified in the ABCA1 gene, which affects its biological function and is associated with several hereditary diseases (such as familial hypo-alpha-lipoproteinaemia and Tangier disease) and increased risk of cardiovascular diseases (CVDs). This review summarises recently identified mutations and SNPs in their connection to atherosclerosis and associated CVDs. Also, we discuss the recently described application of various plant-derived compounds to modulate ABCA1 expression in different in vitro and in vivo models. Herein, we present a comprehensive overview of the association of ABCA1 mutations and SNPs with CVDs and as a pharmacological target for different natural-derived compounds and highlight the potential application of these phytochemicals for treating atherosclerosis through modulation of ABCA1 expression.

Genetic and Functional Analyses of Patients with Marked Hypo-High-Density Lipoprotein Cholesterolemia.

AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

A case report of Tangier disease presents with acute sensorimotor polyneuropathy and its treatment approach.

Polyneuropathy is a frequently encountered clinical presentation where peripheral nerves are affected due to the same cause and physiopathological processes. We report a case of acute sensorimotor polyneuropathy in a patient with Tangier disease (TD) who was treated with miglustat which is a glycosphingolipid synthesis inhibitor. TD is a very rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes the cholesterol efflux regulatory protein. It leads to accumulation of cholesterol esters within various tissues and affects lipid metabolism by deficiency of high-density lipoprotein (HDL) in the blood. Due to the accumulation of cholesterol esters in Schwann cells, it could provoke polyneuropathy in TD. Our case presented to our clinic with quadriparesis and after treated with miglustat therapy his weakness regressed.

Very low HDL levels: clinical assessment and management

ABSTRACT In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree of association between the HDL system and atherosclerotic risk, but as they were not designed to modify lipoprotein functionality, there is insufficient data to establish a causal relationship. We currently have randomized clinical trials of therapies that increase HDL-C concentration by various mechanisms, and this HDL-C elevation has not independently demonstrated a reduction in the risk of cardiovascular events. Therefore, this evidence shows that (a) measuring HDL-C as a way of estimating HDL-related atheroprotective system function is insufficient and (b) we still do not know how to increase cardiovascular protection with therapies aimed at modifying HDL metabolism. This leads us to a greater effort to understand the mechanisms of molecular action and cellular interaction of HDL, completely abandoning the traditional view focused on the plasma concentration of HDL-C. In this review, we will detail this new understanding and the new horizon for using the HDL system to mitigate residual atherosclerotic risk.

HDL: o yin-yang da doença cardiovascular / HDL: the yin-yang of cardiovascular disease

Estudos epidemiológicos mostram relação inversa entre níveis plasmáticos de HDL-colesterol (HDL-C) e incidência de doença cardiovascular (DCV). O papel antiaterogênico da HDL é atribuído às suas atividades anti-inflamatória, antitrombótica e antioxidante, além de sua participação no transporte reverso de colesterol (TRC), processo pelo qual a HDL remove colesterol dos tecidos periféricos, incluindo macrófagos da íntima arterial, e o transporta para o fígado para ser excretado pela bile. Com base nesses fatos, o HDL-C tornou-se alvo atrativo para a prevenção da DCV. No entanto, o fracasso do torcetrapib, droga que aumenta substancialmente os níveis de HDL-C, em prevenir DCV, além do conhecimento gerado por estudos de modelos animais e doenças monogênicas que afetam a concentração de HDL-C, tem suscitado questionamentos sobre o papel antiaterogênico da HDL. Esta revisão tem como objetivo abordar aspectos atuais do conhecimento da HDL, baseando-se nessas recentes controvérsias.

Epidemiological studies demonstrate an inverse correlation between plasma HDL-cholesterol (HDL-C) concentration and incidence of cardiovascular disease (CVD). The antiatherogenic role of HDL has been attributed to its anti-inflammatory, antithrombotic and antioxidant properties, besides its participation in the reverse cholesterol transport (RCT), whereby cholesterol from peripheral tissues (including macrophages of the arterial intima) is delivered to the liver for excretion in bile. Due to these actions, HDL-C has evolved as an attractive target for prevention of CVD. However, the failure of torcetrapib, drug that substantially increases HDL-C levels, in preventing CVD and data from studies with animal models and with carriers of monogenic disorders affecting HDL-C levels in humans provide conflicting data about HDL being antiatherogenic. This review addresses the current state of knowledge regarding HDL based on these recent controversies.