Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

D Serrano,J A Crookshank,R W Mueller,F W Scott,L Marandi,B S Morgan,P Poussier,M.-F Paré

doi:10.1038/s41598-019-51143-7

Abstract

In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARɣ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

Highlights

Type 1 diabetes (T1D) is a multi-system disease involving the pancreas, gut, diet and microbial agents[1,2]
In the present study we further investigated changes in hepatic immunity and metabolism in very young BBdp rats compared with control BBc rats and in NOD mice compared with C57BL/6J control mice
There was a decrease in macrophage cells in neonates which persisted at 30 days (Fig. 1a,b)

Summary

Introduction

Type 1 diabetes (T1D) is a multi-system disease involving the pancreas, gut, diet and microbial agents[1,2]. The large concentration of gut-derived molecules that enter the liver via the portal vein requires a robust immune response to pathogens while maintaining a state of unresponsiveness to harmless dietary components and commensal microbes Any change in this finely tuned balance could play a significant and previously unappreciated role in the pathogenesis of T1D. Findings indicated that in addition to disrupted metabolism and ER stress in the pancreas[3], very young BBdp rats demonstrated deficiencies in hepatic macrophages and increased proinflammatory cytokines, suggesting the usual tolerogenic state was impaired. NOD mice had decreased numbers of liver macrophages and increased lipid accumulation in the neonatal period, followed by upregulated UPR gene expression in the pancreas at 30 days These findings indicate that a more detailed investigation of metabolic dysregulation in liver in T1D pathogenesis is warranted

Methods

Results

Conclusion