High-density lipoprotein-based drug discovery for treatment of atherosclerosis

Du, Yu; Wang, Li; Hong, Bin

doi:10.1517/17460441.2015.1051963

Cited by 8 publications

(7 citation statements)

References 130 publications

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“…However, future studies that precisely assess the effect of other comorbidities and the effect of probable modifiers (e.g., gender) on this association are urgently needed. In addition, the impact of novel lipid‐lowering therapies on HDL composition and functionality, and the overall effect on cognitive function deserves scrutiny. Indeed, further investigations must determine whether HDL and related molecules play a causal role in the pathogenesis of neurodegenerative diseases or whether HDL represents an early‐stage biomarker of these pathologies.…”

Section: Discussionmentioning

confidence: 99%

Emerging roles for high‐density lipoproteins in neurodegenerative disorders

et al. 2019

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Lipoproteins are the complexes of different lipids and proteins, which are devoted to the transport and clearance of lipids or lipid‐related molecules in the circulation. Lipoproteins have been found to play a crucial role in brain function and may influence myelination process. Among lipoproteins, high‐density lipoproteins (HDLs) and their major protein component, apoA‐I, are directly involved in cholesterol efflux in the brain. It has been suggested that inadequate or dysfunctional brain HDLs may contribute to cerebrovascular dysfunctions, neurodegeneration, or neurovascular instability. HDL deficiency could also promote cognitive decline through impacting on atherosclerotic risk. The focus of this review is to discuss knowledge on HDL dysregulation in neurological disorders. A better understanding on how changes in cellular HDL and apolipoprotein homeostasis affect central nervous system function may provide promising novel avenues for the treatment of specific HDL‐related neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Emerging roles for high‐density lipoproteins in neurodegenerative disorders

et al. 2019

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“…The potential anti-atherogenic effects of HDL have been linked to its main functional and structural protein, apolipoprotein A-I (ApoA-I) [ 4 ]. Amongst others, ApoA-I is the acceptor for ATP-binding cassette transporter (ABCA1)-mediated cholesterol efflux and as such, regulates cholesterol efflux capacity [ 5 ]. In addition, ApoA-I has many other functional and cardioprotective effects such as blunting inflammation [ 6 ] and lowering coagulant activity [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells

Tayyeb

Popeijus

Mensink

et al. 2020

IJMS

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Concentrations of apolipoprotein A-I (ApoA-I) decrease during inflammation, which may lead to dysfunctional ApoA-I-poor high-density lipoprotein (HDL) particles, and as such, elevate cardiovascular risk. Therefore, rescuing ApoA-I concentrations, especially during inflammation, seems beneficial. Recently, short-chain fatty acids (SCFAs) have received more attention as a strategy in reversing atherosclerosis. We here evaluated the effects of SCFAs on inflammatory pathways in relation to ApoA-I transcription. SCFAs dose–response studies were performed in the presence and absence of inflammatory cytokines. ApoA-I and interleukin 8 (IL-8) mRNA expression were analyzed using qPCR and ELISA, respectively. To study underlying mechanisms, nuclear factor kappa B (NF-κB) transactivation and changes in mRNA expressions of the genes targets of bromodomain and extra-terminal (BET) inhibition, peroxisome proliferator-activated receptor-alpha (PPARα) transactivation and activator protein 1 (AP-1) pathway were analyzed. SCFAs (except hexanoic acid) increased ApoA-I mRNA transcription in both normal and inflammatory conditions and lowered IL-8 mRNA expression. This anti-inflammatory effect of SCFAs was confirmed by inhibition of NF-κB transactivation. Moreover, butyric acid increased carnitine palmitoyltransferase 1 (CPT1), PPARα target gene, mRNA transcription in both conditions, and there was a negative correlation between CPT1 and NF-κB. Therefore, PPARα transactivation is probably involved in the anti-inflammatory effects of SCFAs, which rescues ApoA-I transcription. In conclusion, propionate, butyrate and valerate elicit anti-inflammatory effects which might rescue ApoA-I transcription in inflammatory conditions via PPARα transactivation mediated NF-κB inhibition.

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“…However, a number of recent studies demonstrated that the level of circulating HDL-C alone represents an inadequate indicator of therapeutic efficacy ( 2 ). Instead, the functionality of HDL is more informative than circulating HDL-C levels in the evaluation of therapeutic approaches for atherosclerosis ( 3 ). HDL has multiple atheroprotective effects.…”

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confidence: 99%

AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice

Ma¹,

Wang²,

Liu³

et al. 2017

Journal of Lipid Research

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HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. However, the effect of AMPK activation on HDL functionality has not been established in vivo. We assessed the effects of pharmacological AMPK activation using A-769662, AICAR, metformin, and IMM-H007 on the atheroprotective functions of HDL in apoE-deficient (apoE−/−) mice fed with a high-fat diet. After administration, there were no changes in serum lipid levels among the groups. However, mice treated with AMPK activators showed significantly enhanced reverse cholesterol transport in vivo and in vitro. AMPK activation also increased the expression of ABCA1 and ABCG1 in macrophages and scavenger receptor class B type I and LCAT in the liver. HDL from AMPK activation mice exhibited lower HDL inflammatory index and myeloperoxidase activity and higher paraoxonase 1 activity than HDL from untreated mice, implying superior antioxidant and anti-inflammatory capacities. Pharmacological AMPK activation also induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE−/− mice. These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. This likely represents a key mechanism by which AMPK activation attenuates atherosclerosis.

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High-density lipoprotein-based drug discovery for treatment of atherosclerosis

Cited by 8 publications

References 130 publications

Emerging roles for high‐density lipoproteins in neurodegenerative disorders

Emerging roles for high‐density lipoproteins in neurodegenerative disorders

Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells

AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice

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