| Title: | Impact of naturally occurring genetic variations in hepatic transporters on cholesterol and glucose homeostasis, fatty liver, cardiovascular health, and lifespan. |
| Lead Institution: | University Medicine Greifswald |
| Principal investigator: |
Application 319358
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About
Impairment in the body's energy homeostasis (as seen in metabolic syndrome) leads to increased fat accumulation in the body, especially in the liver. Consequently, the risk for liver, kidney, and heart diseases increases, and life expectancy decreases. Many risk factors for metabolic syndrome, e.g. increased alcohol consumption or high caloric intake, are already known, but individuals react differently to these risk factors. The mechanisms behind this individual response remain largely unknown. Proteins called transporters carry their substrates in or out of the cell through the cell membrane. Impairments of transporters result in changes to cell function. We focus on selected transporters, namely OCT1-3, OCNT1-2, OATP1B1, and MRP4, which are either specifically localized in the liver or present in many organs, including the liver. Their substrates include several commonly used drugs, such as cholesterol-lowering statins, glucose-lowering metformin, as well as molecules that play a role in human metabolism. The selected liver transporters have previously been linked to impaired energy homeostasis. For example, OCT1 was linked to fatty liver disease in animal models. Reduced OCTN2 activity could also be associated with fatty liver as well as muscle weakness and impairment of heart muscle cells. Finally, OATP1B1 and MRP4 transport statins to and from their working sites. Altered activity of OATP1B1 and MRP4 has been shown to affect treatment efficacy. All these transporters are highly genetically variable, resulting in a considerable portion of the population having altered or impaired transporter function. Although these individuals are healthy, the effectiveness of transported drugs or metabolic pathways can be altered. Our aim is to identify connections between the body's energy homeostasis and these transporters. We want to show that genetic alterations influence parameters of fat and energy homeostasis in blood and organs. Consequently, we propose effects on the risk of cardiovascular events, inflammatory processes, and life expectancy. To achieve this, we plan to use genotyping data from the UK Biobank to assess the alterations in these transporters in relation to metabolic homeostasis, inflammation, as well as health outcomes and mortality data. We hope that within the first three years of the project, we can gain first insights into the role of liver transporters in the development and progression of metabolic impairment and associated mortality. Additionally, we hope to identify opportunities for more individualized treatment and present novel therapeutic targets for these conditions.1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 20965 | Genetically Determined Loss-of-Function of the Organic Cation Transporter OCT1 Is Associated with Lower Liver Fat Content in Humans | Anna K. Scheurer-Böhme (+11) | 2026 | International Journal of Molecular Sciences |
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