Liraglutide attenuates renal tubular ectopic lipid deposition in rats with diabetic nephropathy by inhibiting lipid synthesis and promoting lipolysis

Abstract

Liraglutide is a new hypoglycemic drug. The previous studies have shown that liraglutide can improve the renal outcomes of patients with type 2 diabetes. Recently, it was approved by the U.S. FDA for used as a weight-loss drugs. However, the mechanism of its improvements of renal function in diabetic nephropathy patients is unclear. In addition, the effect of liraglutide on lipid metabolism is also not clear. The purpose of this study was to investigate the effects and mechanisms of liraglutide in alleviating ectopic lipid deposition (ELD) in rats with diabetic nephropathy (DN). Male Sprague-Dawley (SD) rats were treated with high-fat diet + unilateral nephrectomy + low-dose STZ combined to establish a DN rat model to evaluate the lipid-lowering effect of liraglutide. Liraglutide at 0.4 mg/kg/d were subcutaneous injected into for 12 weeks (DN + liraglutide group). After the DN rat model was established, body weight loss, 24-h urine volume increasing, serum triglycerides (TG) and serum total cholesterol (TCh) increasing, ectopic lipid droplet deposition in renal tubular increasing, mesangial proliferation in renal tissue were observed in DN rats. The treatment with liraglutide could reduce the body weight and the average daily food intake of the rats, as well as TG, TCh, and ectopic lipid droplet deposition in renal tubular. Metabolomics result showed that serum differential metabolites between the DN - vehicle control group and the DN + liraglutide group mainly included serine, threonine, phenylalanine, oxyproline, threonine, sorbitol, glyceryl monostearate, glycerol monostearate, and β-d-glucuronic acid. Moreover, liraglutide can reduce plasma lipid levels in DN rats by increasing the products of lipolysis including 1-monopalmitin and 1-monoostearin. Immunohistochemistry and Western blot showed that the expression levels of lipid synthesis-related sterol regulatory element binding protein 1 (SREBP-1) and fatty acid synthase (FAS) were significantly increased, and lipolysis-related adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) were significantly decreased both in the renal tissue of DN rats and PA-induced HK-2 cells (lipid droplet accumulation model). However, liraglutide can attenuate renal tubular ectopic lipid deposition in DN rats by inhibiting SREBP-1, FAS and increasing ATGL, HSL protein expression level, and also ameliorated PA-induced lipid accumulation in renal tubular epithelial cells. These lipid metabolism changes were attributed to liraglutide by upregulating AMP-activated protein kinase (AMPK) phosphorylation in the kidney of DN rats. Collectively, these findings confirm that liraglutide inhibits lipid synthesis and promotes lipolysis to attenuate renal ectopic lipid deposition in DN rats by promoting AMPK phosphorylation.