bims-liverm 2023-09-03 papers

Issue of 2023–09–03
two papers selected by

Trends Endocrinol Metab. 2023 Aug 29. pii: S1043-2760(23)00155-8. [Epub ahead of print]

The emerging role of bile acids in white adipose tissue.

Andreas Schmid, Thomas Karrasch, Andreas Schäffler.

The effects of bile acids (BAs) on liver, enteroendocrine function, small intestine, and brown adipose tissue have been described extensively. Outside the liver, BAs in the peripheral circulation system represent a specific but underappreciated physiological compartment. We discuss how systemic BAs can be regarded as specific steroidal hormones that act on white adipocytes, and suggest the name 'bilokines' ('bile hormones') for the specific FXR/TGR5 receptor interaction in adipocytes. Some BAs and their agonists regulate adipocyte differentiation, lipid accumulation, hypoxia, autophagy, adipokine and cytokine secretion, insulin signaling, and glucose uptake. BA signaling could provide a new therapeutic avenue for adipoflammation and metaflammation in visceral obesity, the causal mechanisms underlying insulin resistance and type 2 diabetes mellitus (T2D).

Keywords: FXR; TGR5; adipocyte; adipoflammation; bile acids; white adipose tissue

DOI: https://doi.org/10.1016/j.tem.2023.08.002

bioRxiv. 2023 Aug 16. pii: 2023.06.02.543391. [Epub ahead of print]

Mechanism of substrate binding and transport in BASS transporters.

Patrick Becker, Fiona B Naughton, Deborah H Brotherton, Raul Pacheco-Gomez, Oliver Beckstein, Alexander D Cameron.

The Bile Acid Sodium Symporter (BASS) family transports a wide array of molecules across membranes, including bile acids in humans, and small metabolites in plants. These transporters, many of which are sodium-coupled, have been shown to use an elevator mechanism of transport, but exactly how substrate binding is coupled to sodium ion binding and transport is not clear. Here we solve the crystal structure at 2.3 Å of a transporter from Neisseria Meningitidis (ASBT NM ) in complex with pantoate, a potential substrate of ASBT NM . The BASS family is characterised by two helices that cross-over in the centre of the protein in an arrangement that is intricately held together by two sodium ions. We observe that the pantoate binds, specifically, between the N-termini of two of the opposing helices in this cross-over region. During molecular dynamics simulations the pantoate remains in this position when sodium ions are present but is more mobile in their absence. Comparison of structures in the presence and absence of pantoate demonstrates that pantoate elicits a conformational change in one of the cross-over helices. This modifies the interface between the two domains that move relative to one another to elicit the elevator mechanism. These results have implications, not only for ASBT NM but for the BASS family as a whole and indeed other transporters that work through the elevator mechanism.

DOI: https://doi.org/10.1101/2023.06.02.543391