Abstract 11813: Inflammation Induced by Free-fatty Acid-tlr4/myd88 Signaling in Non-immune Cells Play a Pivotal Role in Both Cardiovascular and Metabolic Diseases

Abstract

Serum free fatty acid (FFA) levels are increased in obese subjects and associated with increased risks of cardiovascular and metabolic diseases. Previous studies have shown that FFAs induce cellular dysfunction and apoptosis (“lipotoxicity”) in vitro. However, its precise role is unclear in pathologies in vivo. To investigate the concrete mechanisms of lipotoxicity in vivo,we first established a novel method to selectively increase the circulating free palmitate level and found that palmitate rapidly induces β[[Unable to Display Character: ]]cell dysfunction via TLR4/MyD88 pathway in mice. However, the TLR4/MyD88 pathway was dispensable for cell autonomous effects of palmitate on β cells in vitro. Instead, TLR4/MyD88 mediates production of CCL2 and CXCL1 in response to palmitate in β cells. Indeed, flow cytometric analysis showed that palmitate induced accumulation of CD11b+Ly-6C+ M1-type inflammatory macrophages within islets, which was not observed in Tlr4-/- or Myd88-/- mice. Bone marrow transplantation experiments confirmed that TLR4 expressed on islet cells but not myeloid cells are required for the recruitment of macrophages to the islets. Moreover, depletion of M1 macrophages protected mice from palmitate-induced β cell dysfunction, indicating the causative involvement of M1 macrophages in β cell dysfunction. Coculture experiments combined with IL-1β and TNFα neutralizing antibody demonstrated reciprocal interactions between β cells and M1 macrophages, which form vicious cycle that enhance inflammatory processes and β cell dysfunction. Finally, we showed that same mechanisms are playing causative roles in β cell dysfunction in db/db and KKAy mice, T2D models. Those results demonstrate a model in which β cells respond to saturated FFAs and recruit macrophages, and subsequent interactions propagate inflammation within islets that lead to β cell dysfunction. We also found that palmitate similarly activates inflammatory processes in injured arteries, resulting in a marked aggravation of neointima formation. Our results clearly demonstrate that inflammation is the essential mechanism of lipotoxicity in vivo and the saturated FFA-TLR4/MyD88 pathway may play a pivotal role in both cardiovascular and metabolic diseases