Therapeutic potential of S100A10 Inhibition in Hepatic Insulin Resistance, MASLD and Type 2 Diabetes

Background

Obesity is a major risk factor for the development of Metabolic dysfunction Associated Steatotic Liver Disease (MASLD), affecting one quarter of the global population worldwide. It initiates with ectopic fat accumulation in the liver (steatosis) and can progress toward steatohepatitis (inflammation and fibrosis). Steatosis promotes insulin-resistance, a key event in the development of Type 2 Diabetes (T2D).

In this context, our recent findings underscored a role for the protein S100A10 in MASLD development and thus, in T2D. As S100A10 can be released in the circulation upon damages, it has been shown that S100A10 can trigger deleterious effects on other cells through autocrine, paracrine or endocrine effect.

Hypothesis

Based on our preliminary data, we suggested that intra-cellular and secreted fraction of S100A10 in the liver have different outcomes on MASLD, insulin resistance and T2D.

Methods

In our laboratory, we recently implemented the utilization of Human Liver Organoids (HLOs), derived from embryonic stem cells, and composed of the main cell types of the liver. Using the HLOs we recapitulate MASLD formation and aim to better define the appropriate therapeutic strategy to target S100A10. In order to hamper the intra-cellular activity of S100A10 we use a pharmacological inhibitor, whereas the extra-cellular actions are investigated with recombinant S100A10 and neutralizing antibodies.

Results

We optimized MASLD formation in the HLOs, in which we recapitulated different steps of the disease formation. Our preliminary data showed a regulation of steatosis by the extra-cellular fraction of S100A10 while it did not contribute to fibrosis development. On the contrary, targeting intra-cellular S100A10 with pharmacological inhibitor rescued fibrosis without affecting steatosis. 

Conclusions

We discovered specific functions of S100A10 within and outside of the cell, driving liver disease progression.

Importance

The findings of this study pave the way for further investigations of the proper contribution of intra-cellular versus secreted S100A10 in order to design relevant therapeutic approaches. By targeting circulating S100A10 with a neutralizing antibody, we might reduce lipid accumulation in the liver. Besides, we might also improve the functionality of other organs involved in the regulation of glucose homeostasis, which we are currently investigating.