Penn State Discoveries Reveal Self-Pairing FXR, Opening New Therapeutic Paths

A protein named farnesoid X receptor (FXR), crucial for regulating fat, glucose, and cholesterol, has been found by Penn State researchers to pair with itself, in addition to its known partnership with the retinoid X receptor alpha (RXR) protein. The team has characterized the structure of this FXR-FXR pairing, observing that despite its distinct conformation, it can still activate gene expression.

This finding could create new therapeutic paths for liver cancer, diabetes, and other metabolic diseases by specifically targeting this self-paired FXR, potentially with fewer unintended side effects.

The research was published in the journal Nucleic Acids Research on February 23.

FXR's Established Role

FXR is predominantly found in the liver, kidneys, and intestine, where it helps maintain lipid, glucose, and bile acid balance. Its primary function involves partnering with RXR to form a complex. This FXR-RXR complex binds to specific DNA sequences and acts as a receptor for ligands. Once ligands bind, the complex recruits cellular machinery to regulate genes involved in bile acid synthesis and lipid and glucose metabolism.

Overcoming Therapeutic Challenges

Targeting the FXR-RXR complex for therapeutic purposes has been complicated by RXR's extensive roles, as it partners with numerous other receptor proteins. Disrupting RXR's function could lead to broad, undesired consequences. Prior studies had hinted at FXR's ability to partner with another FXR molecule, prompting the current investigation into the structure and function of the FXR-FXR complex as a potential novel therapeutic target.

Confirming the FXR-FXR Pairing

In laboratory experiments, purified FXR was combined with synthetic DNA segments containing the known FXR binding sequences. The researchers confirmed that FXR could bind to DNA both individually and as a pair. A separate experiment demonstrated that the FXR-FXR pairing was capable of recruiting the necessary cellular components and driving gene expression.

A Unique Conformation Unveiled

Using small-angle X-ray scattering, the team characterized the three-dimensional structure of the FXR-FXR complex. The analysis revealed that the molecules adopt an extended conformation, which is significantly different from the FXR-RXR complex. Unlike other characterized receptor protein pairings, the ligand-binding regions of the FXR-FXR proteins are separated and do not interact with each other.

Implications for Disease Treatment

This unique conformation suggests that the FXR-FXR pairing might regulate a different set of genes compared to the FXR-RXR pair. Future research will explore which specific genes are regulated and the distinct roles these two types of pairings may play. This discovery could uncover previously unknown functions of the FXR receptor, offering new avenues for understanding and treating diseases associated with FXR, including liver disease, diabetes, and other metabolic conditions.

Research Team and Funding

The research team at Penn State included Denise Okafor, Sabab Hasan Khan, and Neela Yennawar. Funding for the study was provided by the U.S. National Institutes of Health, the U.S. National Science Foundation, and the Penn State Huck Institutes of the Life Science.