Nuclear receptor PXR in obesity and its regulation by metabolic status

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Auditorium F202 (Aapistie 5B). Remote access: https://oulu.zoom.us/j/62058883857?pwd=ZEo2b1dnV3k0Nk45eVRmNHBjdWVIdz09

Topic of the dissertation

Nuclear receptor PXR in obesity and its regulation by metabolic status

Doctoral candidate

Master of science Mikko Karpale

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, Research unit of biomedicine

Subject of study

Medicine

Opponent

Professor Paavo Honkakoski, University of Eastern Finland, Faculty of health sciences, School of pharmacy

Custos

Professor Jukka Hakkola, University of Oulu, Faculty of medicine, Research unit of biomedicine

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Chemical environment-sensing receptor interferes with normal metabolism – worrying indications of increased harm from chemicals in the obese

Many chemicals, such as environmental contaminants and some drugs, increase the risk of developing metabolic diseases, like type 2 diabetes, but the mechanism is unknown. A recent doctoral thesis study investigated a receptor that senses the chemical environment in obese mice and found that diet-induced obesity sensitizes mice to detrimental metabolic properties of receptor activation.

Pregnane X receptor (PXR), activated by environmental chemicals, disrupted the metabolism of obese mice by inducing fatty liver, accelerating cholesterol synthesis, and altering glucose metabolism. In addition, the study discovered a molecular mechanism that explains chemical-induced elevations in cholesterol. The increase in cholesterol synthesis observed in mice was also repeated in a clinical study in healthy volunteers that showed an increase in harmful LDL cholesterol.

-It has been known that many chemicals that activate PXR may raise cholesterol and LDL cholesterol, but this is the first time that PXR has been shown to mediate the effect, explains doctoral student Mikko Karpale from the University of Oulu.

The effects of PXR on metabolism have previously been studied mainly in subjects with normal weight. The study characterized the effects of activation in obese mice, as obesity is a major predisposing factor for metabolic diseases.

Diet-induced obesity sensitized mice to detrimental metabolic properties of PXR activation, and activation affected key factors of metabolic health.

-We don’t know yet if this is true for humans also, but the result provides worrying indications of the potential aggravated harms of the chemicals in the obese, Karpale says.

The study provided important new insights into the molecular mechanisms of chemical-induced harm. The results can be used to identify the risks associated with chemicals and to assess and avoid potential harm from chemicals. In addition, the receptor may serve as a drug target in the future. However, further studies are needed to elucidate the effect of PXR activation on the morbidity of metabolic diseases in humans.
Last updated: 12.8.2021