**8.4 miRNA inhibitors**

HDL is a major carrier of circulating miRNAs in plasma as mentioned above. Meanwhile, miRNAs have also emerged as the important regulators on HDL metabolism. Several studies demonstrated that miRNAs control the expression of a large number of genes associated with HDL metabolism, including ABCA1, ABCG1, and SR-BI [209, 210]. These findings strongly suggested that miRNAs regulate HDL biogenesis, cholesterol efflux, and uptake in the liver, thereby controlling the whole RCT process [211, 212].

miR-33 could repress the expression of ABCA1/ABCG1 proteins; however, knockout of miR-33 upregulates ABCA1/ABCG1 expression, promotes HDLmediated cholesterol efflux, increases plasma HDL-C levels, and prevents the progression of atherosclerosis [213–215]. Besides raising HDL-C levels, inhibition of miR-33 also lowers VLDL-TG contents in nonhuman primates [216]. Furthermore, anti-miR-33 therapy inhibits the gene expressions that enhance mitochondrial respiration and ATP production, promotes macrophage cholesterol efflux accompanying with ABCA1 upregulation, and reduces atherosclerosis [217]. In addition, miR33 inhibition overcomes the deleterious effects of atherosclerosis plaque progression in LDL-R knockout mice and diabetic mice [218, 219].

Additionally, inhibiting miR-144 could upregulate hepatic ABCA1 expression and increase HDL-C levels through the FXR-dependent pathway [220]. However, overexpression of miR-144 in the liver reduces ABCA1 expression, attenuates cholesterol efflux in macrophages, reduces HDL-C levels, and promotes atherosclerosis development [221]. An increase in miR-145 decreases ABCA1 expression and reduces plasma HDL-C levels and glucose-stimulated insulin secretion in islets. However, inhibiting miR-145 produces the opposite effects of increasing ABCA1 expression, promoting HDL biogenesis in the liver and improving glucose-stimulated insulin secretion in islets [222]. In mice, inhibition of miR-148a increases the hepatic expression of LDL-R and ABCA1, subsequently decreases plasma LDL-C concentrations, and elevates HDL-C levels, which may decrease LDL-C/HDL-C ratio and CVD risk [223]. Furthermore, miR-185, miR-96, and miR-223 may repress selective HDL-C uptake through inhibiting hepatic SR-BI, implying a novel mode of SR-BI regulation and an important role of miRNAs in modulating cholesterol metabolism [224]. Thus, these findings strongly supported the idea of developing miRNA inhibitors for the treatment of dyslipidemia and atherosclerosis [225].

### **9. Conclusions**

As the failure of CEPT inhibitors on reducing CVD risk, the traditional concept of HDL against CVD from Framingham study has been challenged. Besides, abnormal HDL functions in the setting of systemic diseases also make HDL more confused to be understood. Consequently, whether HDL-C is still a good predictor for CVD and whether HDL could really provide valuable protections against CVD are questioned. HDL comprises a heterogeneous group of particles composed of various of bioactive components. The compositional complexity of HDL is almost hardly to be reflected by measuring cholesterol contents loading in HDL. Thus, quantifying HDL-P numbers and evaluating HDL functions might be the more meaningful markers for CVD prediction. Meanwhile, many emerging strategies targeted to regulate HDL metabolism and increase HDL-P levels were also attempted. Expectedly, more available measurement methods and therapeutic agents about HDL would arise in the near future.

### **Acknowledgements**

This project was supported by grant 31200884 from the National Natural Science Foundation of China; by grant 2018Y9100 from the Joint Funds for the Innovation of Science and Technology, Fujian Province; and by grant 2019HSJJ04 from highlevel hospital foster grants of Fujian Provincial Hospital, Fujian Province, China.

**27**

*High-Density Lipoprotein: From Biological Functions to Clinical Perspectives*

I thank Dr. Yansong Guo and Dr. Na Lin for the kind help on editing and polish-

*DOI: http://dx.doi.org/10.5772/intechopen.91136*

**Notes/thanks/other declarations**

**Appendices and nomenclature**

AAT alpha-antitrypsin

apoA-I apolipoprotein A-I apoB apolipoprotein B

CE cholesteryl esters

COX-2 cyclooxygenase-2 CVD cardiovascular disease

HDL-P HDL particles

HL hepatic lipase HOCl hypochlorous acid

ABCA1 ATP-binding cassette transporter A1 ABCG1 ATP-binding cassette transporter G1

BET bromodomain and extra-terminal

CETP cholesterol ester transfer protein cIMT carotid intima-media thickening

eNOS endothelial nitric oxide synthase EPCs endothelial progenitor cells FGF fibroblast growth factor FXR Farnesoid X receptor HDL high-density lipoprotein

HDL-C high-density lipoprotein cholesterol

HUVECs human umbilical vein endothelial cells ICAM-1 intercellular adhesion molecule-1

LCAT lecithin cholesterol acyltransferase

MACE major adverse cardiovascular events

PAF-AH platelet-activating factor acetylhydrolase PAI-1 plasminogen activator inhibitor-1 PEDF pigment epithelium-derived factor

LDL-R low-density lipoprotein receptor

HII HDL inflammatory index

I/R ischemic/reperfusion

LDL low-density lipoprotein

LysoPC lysophosphatidylcholine

LPS lipopolysaccharide LXR liver X receptor

miRNAs microRNAs MMP metalloproteinases MPO myeloperoxidase NF-κB nuclear factor kappa-B

NO nitric oxide ox-HDL oxidized HDL ox-LDL oxidized LDL PA phosphatidic acid

PGI2 prostaglandin I-2

AMPK adenosine monophosphate-activated protein kinase

ing this manuscript.

#### **Conflict of interest**

The author declares that there are no conflicts of interest.

*High-Density Lipoprotein: From Biological Functions to Clinical Perspectives DOI: http://dx.doi.org/10.5772/intechopen.91136*
