A New Small Molecule Increases Cholesterol Efflux

Groenen, Anouk G.; Westerterp, Marit

doi:10.1161/atvbaha.121.315930

Cited by 2 publications

(2 citation statements)

References 33 publications

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“…Other nonlipogenic ABCA1 inducing compounds have been researched to selectively activate ABAC1 while keeping the liver unaffected. A new small molecule ABCA1 inducer called E17241 dose-dependently upregulates ABCA1 expression and increases cholesterol efflux [ 87 ]. Administered at two different doses, this drug enhances ABAC1 expression without provoking any adverse effects on the liver.…”

Section: Resultsmentioning

confidence: 99%

Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer’s Disease

Passero,

Zhai,

Huang

2023

IJERPH

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Despite extensive research and seven approved drugs, the complex interplay of genes, proteins, and pathways in Alzheimer’s disease remains a challenge. This implies the intricacies of the mechanism for Alzheimer’s disease, which involves the interaction of hundreds of genes, proteins, and pathways. While the major hallmarks of Alzheimer’s disease are the accumulation of amyloid plaques and tau protein tangles, excessive accumulation of cholesterol is reportedly correlated with Alzheimer’s disease patients. In this work, protein-protein interaction analysis was conducted based upon the genes from a clinical database to identify the top protein targets with most data-indicated involvement in Alzheimer’s disease, which include ABCA1, CYP46A1, BACE1, TREM2, GSK3B, and SREBP2. The reactions and pathways associated with these genes were thoroughly studied for their roles in regulating brain cholesterol biosynthesis, amyloid beta accumulation, and tau protein tangle formation. Existing clinical trials for each protein target were also investigated. The research indicated that the inhibition of SREBP2, BACE1, or GSK3B is beneficial to reduce cholesterol and amyloid beta accumulation, while the activation of ABCA1, CYP46A1, or TREM2 has similar effects. In this study, Sterol Regulatory Element-Binding Protein 2 (SREBP2) emerged as the primary protein target. SREBP2 serves a pivotal role in maintaining cholesterol balance, acting as a transcription factor that controls the expression of several enzymes pivotal for cholesterol biosynthesis. Novel studies suggest that SREBP2 performs a multifaceted role in Alzheimer’s disease. The hyperactivity of SREBP2 may lead to heightened cholesterol biosynthesis, which suggested association with the pathogenesis of Alzheimer’s disease. Lowering SREBP2 levels in an Alzheimer’s disease mouse model results in reduced production of amyloid-beta, a major contributor to Alzheimer’s disease progression. Moreover, its thoroughly analyzed crystal structure allows for computer-aided screening of potential inhibitors; SREBP2 is thus selected as a prospective drug target. While more protein targets can be added onto the list in the future, this work provides an overview of key proteins involved in the regulation of brain cholesterol biosynthesis that may be further investigated for Alzheimer’s disease intervention.

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Section: Resultsmentioning

confidence: 99%

Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer’s Disease

Passero,

Zhai,

Huang

2023

IJERPH

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“… Substance use* Tobacco [ 315 , 316 ], marijuana [317] , [318] , [319] , alcohol [320] , cocaine [321] Autoimmune disease* Rheumatoid arthritis [ 322 , 323 ], Systemic Lupus Erythematosus [324] , psoriasis and psoriatic arthritis [ 325 , 326 ], ankylosing spondylitis [327] , scleroderma [328] , inflammatory bowel disease [329] , probably others immunological disease and inflammation elsewhere in the body [ 82 , 159 ]; clonal hematopoiesis of indeterminate potential (CHIP) [160] , [161] , [162] , [163] ; neutrophil extracellular traps [164] , [165] , [166] , [167] These are not yet readily actionable and further research is needed. Genetic factors and social determinants of health Knowledge and applicability are developing rapidly, already useful for FH and some other genetic variants [330] , [331] , [332] , [333] , [334] Race/ethnicity (All people are complex genetic mixtures, but some genetic factors are alerted by ethnicity in some cases. While of course not universal or definitive, Race/ethnicity can signal risk requiring deeper evaluation)* South Asian (much higher risk of atherosclerosis, high Lipoprotein (a) and diabetes and at early ages) [ 280 , [335] , [336] …”

Section: Despite Many Recommendations Early Treatment Has Not Become ...mentioning

confidence: 99%

There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness

Makover¹,

Shapiro²,

Tóth³

2022

American Journal of Preventive Cardiology

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A New Small Molecule Increases Cholesterol Efflux

Cited by 2 publications

References 33 publications

Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer’s Disease

Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer’s Disease

There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness

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