Role of xenobiotic-sensing nuclear receptor PXR in lipid, cholesterol, and bone metabolism

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Auditorium F202 of the Faculty of Medicine (Aapistie 5 B)

Topic of the dissertation

Role of xenobiotic-sensing nuclear receptor PXR in lipid, cholesterol, and bone metabolism

Doctoral candidate

Master of Science Heba Nabil Abdelfattah

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine (Pharmacology and Toxicology)

Subject of study

Pharmacology and Toxicology

Opponent

Professor Oliver Burk, Dr. Margarete Fischer-Bosch Institut für Klinische Pharmakologie (IKP) Stuttgart, Germany

Custos

Professor Jukka Hakkola, Research Unit of Biomedicine (Pharmacology and Toxicology), Faculty of Medicine, University of Oulu

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Role of xenobiotic-sensing nuclear receptor PXR in lipid, cholesterol, and bone metabolism

The pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, is a key regulator of drug and xenobiotic metabolism. Additionally, PXR regulates hepatic glucose, lipid, cholesterol, and bile acid metabolism, and inflammation. However, the mechanisms and consequences are still poorly understood.
I investigated the role of PXR in the regulation of lipid metabolism and bone homeostasis. Specifically, I studied the effect of the two different PXR activators, atorvastatin and pregnenolone 16α-carbonitrile (PCN), on the hepatic transcriptome in mice. Furthermore, I studied the roles of PXR and oxysterols on reverse cholesterol transport. I also studied the role of PXR in human osteoblasts cells.
This study demonstrated that atorvastatin (the most prescribed hypocholesterolemic drug in humans) regulates hepatic cholesterol and lipid synthesis PXR-dependently, but the response is distinct from PCN. Unlike PCN, atorvastatin does not induce liver steatosis. Neither PCN nor atorvastatin had a harmful effect on glucose tolerance in the high-fat diet-fed mice.
In healthy volunteers treated with rifampicin, the plasma 4β-hydroxycholesterol (4βHC) was elevated compared to placebo. 4βHC is an agonist of the liver X receptor (LXR), a major regulator of lipid metabolism. In vitro studies revealed that incubation of macrophages with 4βHC represses cholesterol influx and induces efflux in macrophages.
Furthermore, rifampicin increased alkaline phosphatase (ALP) plasma levels, particularly the bone specific-ALP. In vitro studies demonstrated that this is most likely via the direct effect of rifampicin in osteocytes. However, the role of PXR in this process remains unclear.
Altogether, the results presented in this thesis reveal novel roles of PXR in the regulation of cholesterol and lipid metabolism. PXR mediates the atorvastatin effect on the hepatic transcriptome, particularly on the hepatic cholesterol metabolism. Moreover, through the 4βHC- LXR axis, PXR could be a novel link between hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.
Last updated: 30.11.2022