MORG1-A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes.

Eric Jankowski,Nadja Ziller,Sophie Wulf,Gunter Wolf,Ivonne Loeffler

doi:10.3390/biomedicines10010030

Abstract

Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy.

Highlights

Academic Editor: Maria GrauOne of the most important complications of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) is diabetic nephropathy (DN) [1,2]
In diabetic kidneys, increased uptake of fatty acid (FA), de novo synthesis of FAs and triglycerides and decreased expression of master regulators of fatty acid oxidation (FAO) may contribute to lipid storage, contributing to the altered expression of receptors or transporters regulating the influx/efflux of cholesterol [16,17,19,20]
FA synthesis is regulated by Sterol regulatory element binding proteins (SREBPs)-1 and catalyzed through FA synthase (FAS)

Summary

Introduction

Academic Editor: Maria GrauOne of the most important complications of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) is diabetic nephropathy (DN) [1,2]. In contemporary understanding of renal fibrosis, multiple cell types and different mechanisms appear to be responsible for ECM accumulation and remodeling [8,9,10,11,12,13,14,15]. It has been demonstrated that the downregulation of key enzymes and regulators of fatty acid oxidation (FAO), as well as increased lipid accumulation in proximal tubular epithelial cells, is directly linked to TIF [16]. Injured tubular cells display dramatic metabolic rearrangements, including profound suppression of FAO [17]. This altered renal lipid metabolism has been described in DN, where sustained hyperglycemia promotes FA synthesis and triglyceride accumulation [20]. The elevated serum triglycerides, together with free FAs and modified cholesterol, can cause lipid accumulation in non-adipose tissues, a process termed lipotoxicity [20]

Objectives

Methods

Results

Conclusion