Blood - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 14

cholesterol and phospholipids via ATP-binding cassette transporter-A1, whereas
ATP-binding cassette transporter-G1 and -G4 mediate cholesterol efflux to mature
HDL particles. Mature HDLs induce a cholesterol efflux mediated by the scavenger
receptor-B1, an HDL receptor. Small, lipid-poor HDL3 thus represents more
efficient cholesterol acceptors than HDL2 subtype.
Small, dense HDL3 has anti-oxidative activity, transferring oxidized lipids from
the tissues and blood circulation to the liver. HDL3 particles may constitute
the HDL subset mostly responsible for anti-inflammatory activity under normal
conditions. Alterations in HDL composition, such as: (1) decrease in cholesteryl
esters, ApoA1, and enzymes bound to HDLs and (2) an increase in triglyceride
content and serum amyloid-A occur during inflammation. HDL particles undergo
structural and functional changes especially in atherogenic dyslipidemia [ 18 ]. 28
Replacement of cholesteryl esters by triglycerides alters the conformation of
ApoA1, and hence the lipid-binding capacity. The selective uptake of cholesteryl
esters from high-density lipoprotein by scavenger receptor-B1 is strongly af-
fected by dysfunctional triglyceride-rich HDLs [ 19 ]. HDL enzymes (paraoxonase-1,
platelet-activating factor acetylhydrolase, and lecithin cholesterol acyltransferase)
can become dysfunctional and depleted. Serum amyloid-A can replace ApoA1
and other HDL apolipoproteins [ 20 ]. Enrichment of HDL3 in serum amyloid-A 29
reduces cholesteryl ester uptake by hepatocytes, but can increase HDL binding to
macrophages [ 21 ]. Sustained redirection of cholesterol from the liver to macro-
phages corresponds to a maladaptive response in the long term.
Bile acids interacts with triglycerides. 30 Bile acids are not only required in
dietary lipid absorption in the digestive tract and cholesterol homeostasis, but also
also have endocrine functions [ 22 ]. Bile acids bind G-protein-coupled bile-acid re-
ceptor GPBAR1 31 activate mitogen-activated protein kinase (MAPK) modules and
nuclear receptors such as farnesoid X receptor- or NR1h4). 32 Farnesoid X α (FXR α

receptor- induces apolipoprotein-C2 expression. Agent ApoC2 is a coactivator of

lipoprotein lipase that lowers serum triglyceride and VLDL levels.

α

28 Atherogenic dyslipidemia, a major risk factor for cardiovascular diseases, is defined by higher
circulating levels of pro-atherogenic, cholesterol-rich, ApoB + lipoproteins, such as LDLs, and

lower concentrations of anti-atherogenic ApoA1 HDL particles.

29 Lipid-free serum amyloid-A, a ligand for ScaRb1, inhibits HDL binding on ScaRb1 receptor.
HDL-associated SAA has little effect on HDL binding to ScaRb1, but decreases selective
cholesteryl ester uptake of HDL particles.
30 Bile acids are synthesized in the liver from cholesterol. Bile acids secreted from hepatocytes
into the bile canaliculi are stored in the gallbladder and transported down the duodenum. They
are absorbed again in the terminal ileum, and convected back to the liver via the portal vein. Bile
acids decrease their synthesis using a negative feedback. Main bile acids include: (1) primary
bile acids, cholic and chenodeoxycholic acids, as well as their glycine and taurine conjugates and
(2) secondary bile acids, deoxycholic and lithocholic acids.
31 A.k.a. GPCR19, GPR131, and TGR5.
32 In the liver and intestine, activated farnesoid X receptor- α protects against toxic accumulation of
bile acids by transport and excretion of bile acids. Bile acids are also involved in liver regeneration
by activation of farnesoid X receptors, as well as, but to a lower extent and transiently, xenobiotic
receptors CAR [ 23 ].

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