Abstract & Authors:展开
Objective: Gut derived inflammatory factors can impair glucose homeostasis but the underlying mechanisms are not fully understood. Here we investigate how hepatic gene expression is regulated by gut colonization status through myeloid differentiation primary response 88 (MYD88) and how one of the regulated genes, lipopolysaccharide binding protein (Lbp), affects insulin signaling and systemic glucose homeostasis.
Methods: Liver transcriptomics analysis was performed on four groups of mice fed a chow diet: conventionally raised (CONV-R) wild-type, germ free (GF) wild-type, CONV-R Myd88 KO and GF Myd88 KO. Primary hepatocytes were exposed to combinations of lipopolysaccharide (LPS), LBP and the LBP-blocking peptide LBPK95A, and the effect on insulin signaling was determined. To assess how LBP affects glucose metabolism in vivo two mouse models were applied: treatment with LBPK95A and hepatic knockdown of Lbp using CRISPR-CAS9.
Results: We showed that the colonization status regulates gene expression in the liver and that a subset of these genes, including Lbp, is regulated through MYD88. Furthermore, we showed that LBP impairs insulin signalling in hepatocytes in the presence of low levels of LPS and that that the effect of LBP is abolished by LBPK95A. Finally, we showed that both systemic pharmacological blocking of LBP by LBPK95A and CRISPR-CAS9-mediated downregulation of hepatic Lbp improve glucose homeostasis.
Conclusions: Our results demonstrate that the gut microbiota regulates hepatic expression of Lbp through MYD88-dependent signaling. LBP potentiates LPS inhibition of insulin signaling in vitro as well as impairs systemic glucose homeostasis in vivo.
Antonio Molinaro,Ara Koh
Antonio Molinaro,Ara Koh,Hao Wu,Marc Schoeler,Ilaria Faggi,Alba Carreras,Anna Hallen,Fredrik Bäckhed,Robert Caesar