4β-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters

Abstract

Activation of pregnane X receptor (PXR) elevates circulating 4b-hydroxycholesterol (4bHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4bHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4bHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4bHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4bHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4bHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4bHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.

4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor

“…A recent publication by Salonurmi et al . ( 42 ) showed that 4β-HC induces cholesterol efflux from peripheral mononuclear cells in vivo via transcriptional upregulation of ABCA1 and concomitant suppression of influx transporters. In our hands, 4β-HC did not induce ABCA1 expression in primary hepatocytes ( supplemental Fig.…”

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“…Other oxysterols like 4-hydroxycholesterol, 20-( S )-hydroxycholesterol, 22-( S )-hydroxycholesterol, 24-hydroxycholesterol, 24-( S )-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol itself also induced ABCA1 / Abca1 mRNA 205 , 305 , 313 , 315 , 319 - 327 and ABCA1 protein levels. 321 , 328 The increase in ABCA1 protein was functionally confirmed by an enhanced cholesterol 305 , 306 , 313 , 315 , 318 and phospholipid efflux, 311 , 318 as well as reduced total cholesterol influx. 305 Specifically 22-( R )-hydroxycholesterol and cholesterol induced both LXRA/Lxra and LXRB/Lxrb .…”

“…22-( R )-hydroxycholesterol ( Figure 2 ) has been established as the natural gold standard for ABCA1/Abca1 induction through LXR activation, 122 , 205 , 249 , 252 , 259 , 262 - 264 , 268 , 277 , 278 , 305 - 315 while 9- cis retinoic acid ( Figure 2 ) became the natural gold standard for RXR activation. 122 , 245 , 249 , 259 , 262 , 264 , 277 , 278 , 309 , 311 , 313 , 316 The inducing effects were described both on ABCA1/Abca1 mRNA 122 , 205 , 252 , 263 , 264 , 305 , 307 - 311 , 313 , 315 - 317 and ABCA1 protein levels. 122 , 252 , 263 , 264 , 306 , 309 - 311 , 316 , 318 …”

PXR and 4β-Hydroxycholesterol Axis and the Components of Metabolic Syndrome

“…We have recently demonstrated that 4βHC, through its LXR agonism, could be a link between PXR activation and HDL-C metabolism as it regulates the expression of cholesterol transporters in macrophages [ 67 ]. The expression and function of efflux transporter ATP-binding cassette transporter A1 (ABCA1) and ABCG1 were induced by 4βHC in vitro.…”

“…Both ABCA1 and ABCG1 are known transcriptional targets of LXR [ 58 ]. The efflux, facilitated by ApoAI as an acceptor for cholesterol, was augmented by 4βHC more than the efflux to HDL2 [ 67 ]. Furthermore, 4βHC incubation repressed the expression and function of influx transporter lectin-like oxidized LDL receptor-1 (LOX-1).…”