Investigating and examining the role of Hyocholic acid signalling in athero-immunometabolism

We focused particularly on the signalling properties of Hyocholic acid (HCA), a bile acid found as one of the main forms in pigs, and at low concentrations in humans as a minor component of the human bile acid pool. We have recently elucidated a unique mechanism that the administration of HCA in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis (Published in Cell Metabolism 21). Additionally, reduced serum concentrations of HCA were also associated with other metabolic diseases, including obesity (Nature Communications 21), yet its role in atherosclerosis (AS) remains mostly unexplored.

(AS) is one of the major health burdens of the 21st century. Recent studies shed light on the connection between metabolism and immune-inflammatory processes. Immune cell responses are metabolically demanding and require the reprogramming of bioenergetic pathways. Imbalance of this delicate signalling network leads to chronic inflammation; Low-grade inflammation is characterized by increased infiltration and activation of CD4+ immune cells. Specifically, atherosclerotic plaque development or lesions is considered a crucial risk factor for the development of cardiovascular diseases in patients. However, the role of HCA on T cell response in the pathogenesis of AS remains elusive.

Here we found that the serum HCA is higher in healthy adults compared with patients with AS. High serum HCA contributes to the upregulation of the HCA transporter SLC10A7 by human CD4+ T cells. SLC10A7 enables BA transmembrane transporter activity. Antibody-mediated blockade of SLC10A7 mediated inhibition in HCA uptake into CD4+ T cells resulting in CD4+ T cell retention in the atherosclerotic tissues. Additionally, SLC10A7 KO worsens disease severity in the murine model of AS.

Taken together we hypothesis that an imbalance in the signaling networks linking metabolism and inflammation, as typified by the HCA/SLC10A7 axis, results in the establishment of damaging chronic inflammation, which in turn causes the onset and/or persistence of AS inflammation. Targeting the HCA/SLC10A7 pathway via tools unique to us, i.e., genetic approach (CRISPR/Cas9 technology) or pharmaceutical approach (a monoclonal antibody and a small molecule) will provide beneficial therapeutic effects. The central goal of this proposed study is to determine i) the role of SLC10A7 via overexpression/ knockdown approaches and their implications to atherosclerotic plaque development and/or persistence ii) the detailed mechanisms of HCA/SLC10A7-mediated control of immune T cell functions, and iii) their links (i+ii) to human cardio-metabolic traits.

Possible outcome: The co-applicants have previously demonstrated that HCA is a protective factor against obesity and diabetes (Cell Metabolism 2021 and Nature Communications 2021); Metabolic alterations can interfere with Treg migration (Immunity 2017). The HCA/SLC10A7- induced T cell metabolic reprogramming may be a distinctive feature of AS and an insight into HCA as therapy across other metabolic diseases.