Abstract 11879: Lipotoxicity Involves Inflammatory Processes Mediated by TLR4 Signaling in vivo
Chronic inflammation has been shown to be crucially involved in metabolic as well as cardiovascular diseases. 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. Here, we report that inflammatory processes activated by FFAs are the crucial component 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 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. 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 further augment 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 fatty acid-TLR4/MyD88 pathway may play a pivotal role in both cardiovascular and metabolic diseases.
- © 2011 by American Heart Association, Inc.