Erythropoietin Alleviates Dysregulation Of Hepatic Lipid Metabolism

Objective To investigate the effects of erythropoietin (EPO) on hepatic lipid metabolism and explore the underlying mechanism.Methods Eight-week male ob/ob mice were randomly divided into two groups and treated intraperitoneally with 3000 U/kg recombinant human erythropoietin (EPO) (ob/ob+EPO group, n=6) or phosphate buffer saline (PBS) (ob/ob+PBS group. n=6). respectively. Lean littermate C57BL/6 mice were selected as normal group (C57BL/6 group, n=6). Body weight, food intake, serum lipid levels were measured and intraperitoneal glucose tolerance tests (IPGTT) were performed in mice at the end of the 5-week therapy. HepG2 cells were intervened with palmitic acid (PA,0.5 mmol/L) and EPO. Cells were divided into four groups:CON group, CON+EPO group, PA group and PA+EPO (10 U/ml). Steatosis of hepatic cells was observed by hematoxylin and eosin (HE) staining, or Oil Red O staining. The expression of erythropoietin receptor (EPOR), sterol regulatory element-binding protein-1c (SREBP-lc), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC). fatty acid transporter (CD36), fatty acid binding protein 1 (FABP1), carnitine palmitoyltransferase la (CPT-la) and CPT-2 were detected in mice and HepG2 cells by Western blotting. The mRNA levels of SREBP-1c, FAS, ACC, steroyl-coA desaturase-1 (SCD-1), CD36, FABP1, fatty acid transport protein 2/5 (FATP2/5), CPT-1a, CPT-2, acyl-Coenzyme a oxidase 1(ACOX1), carnitine-acylcarnitine translocase (CACT), microsomal triglyceride transfer protein (MTTP) were determined by Real Time-PCR. One-way ANOVA or LSD test were used for data analysis.Results EPO significantly decreased body weight, food intake in ob/ob mice, accompanied by improved glucose tolerance and serum lipid profile. Reduced lipid accumulation in hepatic cells with EPO treatment was observed by HE or Oil red O staining in vivo and in vitro. The protein levels of SREBP-1c, FAS, ACC, CD36 and FABP1 in ob/ob+EPO group were decreased significantly (all P<0.05), while the protein levels of EPOR and CPT-1a were increased (all P<0.05) when compared with PBS controls. Similar results were also found in PA-incubated HepG2 cells with EPO treatment. The mRNA levels of SREBP-lc. FAS. ACC. SCD-1, CD36, FABP1 and FATP5 in ob/ob+EPO group were decreased (all P<0.05), while the mRNA levels of CPT-la and ACOX1 were increased (all P<0.05) compared with those in ob/ob+PBS group.Conclusion EPO may alleviate the excessive lipid deposition in the liver via reducing the expressions of fatty acid transport proteins, together with decreasing the expressions of enzymes involved in lipogenesis. and increasing the expressions of enzymes involved in fatty acid oxidation.