Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes.
In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-alpha, LXR-beta, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-alpha, and LXR-beta, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.
Proctor
Gregory
G
Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Jiang
Tao
T
Iwahashi
Mieko
M
Wang
Zhuowei
Z
Li
Jinping
J
Levi
Moshe
M
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005355:Fibrosis / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology; D057093:Orphan Nuclear Receptors; D050199:Podocytes / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002784:Cholesterol; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C506001:Mlxipl protein, mouse; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse