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Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

From the Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Address correspondence and reprint requests to Dr. Moshe Levi, Departments of Medicine, Physiology and Biophysics, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. E-mail: moshe.levi{at}uchsc.edu

Abbreviations: ABCA, ATP-binding cassette transporter; ACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; ChREBP, carbohydrate response element–binding protein; FAS, fatty acid synthase; FXR, farnesoid X receptor; HMG, 3-hydroxy-3-methylglutaryl; IL, interleukin; L-PK, liver pyruvate kinase; LXR, liver X receptor; PAI, plasminogen activator inhibitor; PAS, periodic acid Schiff; PPAR, peroxisome proliferator–activated receptor; SCD, stearoyl CoA desaturase; SHP, small heterodimer partner; SREBP, sterol regulatory element–binding protein; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

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)- and -, 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)-, LXR-ß, 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-, and LXR-ß, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.

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