Alterations of Lipid and Cholesterol Metabolism in Cachectic Tumor-Bearing Rats Are Prevented by Insulin

Abstract

The ascites hepatoma Yoshida AH130 causes in the host a rapid and progressive body weight loss, associated with reduced food intake, and protein and lipid hypercatabolism. Because insulin regulates glucose as well as lipid and protein metabolism, we suggest that the observed alterations are at least in part secondary to hypoinsulinemia and/or to the increase of counterregulatory hormones in AH130-bearing rats. To verify this hypothesis, controls with free access to food (n = 4), controls with free access to food plus insulin (107 μmol · kg body wt−1 · d−1) (n = 4), controls pair-fed to the tumor-bearing rats (n = 4), pair-fed controls treated with insulin (n= 4), tumor hosts (n = 9), and tumor hosts treated with insulin (n = 6) were used. The Yoshida ascites hepatoma cells (∼108 cells/rat) were inoculated intraperitoneally. Daily food intake and body weight were measured; insulin was injected starting the day of tumor implantation for 6 d. The metabolism of both cholesterol and lipids was investigated in tumor cells, and ascitic fluid and blood serum were investigated at the end of treatment. Insulin prevented the reduction of food intake (19 ± 0.6 vs. 13 ± 0.4 g/d, P < 0.01; AH130 hosts treated and not treated with insulin, respectively), the loss of body weight (202 ± 12 vs. 135 ± 9 g, P < 0.01), lowered the circulating triglycerides (48.3 ± 4.9 vs. 84.5 ± 7.1 mmol/L, P < 0.01), and free fatty acids (561 ± 47 vs. 989 ± 54 mmol/L (P < 0.01), while corrected the decrease of adipose lipoprotein lipase activity (1,240 ± vs. 300 ± pmol FA, P < 0.01) observed in AH130 hosts. Moreover, insulin prevented the decrease in HDL cholesterol (13.2 ± 0.8 vs. 9.3. ± 0.7 mmol/L, P < 0.01) and significantly increased hepatic cholesterol synthesis as evaluated by 14C-acetate incorporation into cholesterol, in both liver (3,337 ± 245 vs. 830 ± 115 Bq/g, P < 0.01) and AH130 cells (11,676 ± 1,693 vs. 4,196 ± 527 Bq/106 cells, P < 0.01). Thus insulin treatment ameliorated many metabolic derangements, with a lengthening of rats survival time (7 ± 1 vs. 11 ± 1 d, P < 0.05) without significantly stimulating tumor growth. These data, together with our previous observations on the effectiveness of insulin on protein turnover perturbations, suggest that many metabolic alterations occurring during cancer cachexia can be avoided by the administration of this hormone.