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To better understand the role of the liver in the hypertriglyceridemia observed in a tumor-bearing state, we have examined tumor-induced alterations in hepatic lipogenesis and fatty acid oxidation. The effects of differing tumor burden as well as tumor excision on the activity and mRNA levels of malic enzyme and carnitine palmitoyltransferase were studied in Fisher 344 rats bearing a methylcholanthrene-induced sarcoma. Serum triacylglycerols and plasma nonesterified fatty acids (NEFA) levels were both elevated with increasing tumor burden (P < 0.05 vs control). The elevation disappeared with tumor removal. Malic enzyme activity of tumor bearers, compared with control rats, declined with an increase in tumor burden. These two variables were negatively correlated (r = -0.90, P < 0.01). The changes in activity were accompanied by positively correlated changes in mRNA levels (r = 0.73, P < 0.01). Carnitine palmitoyltransferase activity was not altered, even in the presence of a large tumor burden. Hepatic lipogenesis, reflected by malic enzyme activity, was tumor-dependent and was significantly reduced during the period of circulating hypertriglyceridemia. Fatty acid oxidation, reflected by carnitine palmitoyltransferase activity, was not enhanced in spite of an ample supply of NEFAs to the liver from the peripheral tissues. The data suggest that neither hepatic lipogenesis nor fatty acid oxidation contribute to hypertriglyceridemia in the tumor-bearing state.

Cancer cachexia is frequently accompanied by hyperlipidemia. To identify the mechanisms underlying this alteration in lipid metabolism, free fatty acid (FFA) and very low density lipoprotein-associated triacylglycerol (VLDL-TG) kinetics were determined in tumor-bearing (subcutaneously implanted methylcholanthrene-induced sarcoma) Fischer 344 rats. The animals were studied after chronic vascular catheterization, in an unanesthetized, undisturbed state, after 24 hr of fasting. They were separated into three groups: control (n = 5), tumor-bearing (n = 5, tumor burden = 10% body weight), and 7 days after tumor excision (n = 5). VLDL-TG and FFA kinetics were assessed by a constant infusion of [3H]palmitate-labeled VLDL-TG and [14C]palmitate bound to albumin, respectively. FFA rate of appearance (FFA-Ra) and clearance (FFA-Cl) and VLDL-TG rate of appearance (VLDL-TG-Ra) and clearance (VLDL-TG-Cl) were determined at steady state. We observed that the tumor-bearing rats had significantly increased FFA-Ra and VLDL-TG-Ra, decreased VLDL-CL, and maintained FFA-Cl, when compared to control. These alterations returned to normal levels after tumor excision. The results suggest that the hyperlipidemia observed in tumor-bearing rats is due to elevated lipolysis rate, maintained rate of plasma FFA clearance, increased triacylglycerol production and VLDL secretion by the liver, and decreased VLDL-TG clearance from plasma. These alterations were reversed 7 days following tumor excision.

A model of reversible, extrahepatic biliary obstruction is described. Vessel loop blockade of the biliary tree results in obstructive jaundice while removal of the exteriorized vessel loop provides internal biliary drainage without subsequent laparotomy. This technique combined with a system for chronic venous infusion and arterial blood sampling in the unrestrained rat is ideal for long-term metabolic studies of obstructive jaundice. Male Fisher 344 rats (275-350 g) underwent either the combined procedure of total biliary tract blockade and vascular access or sham operation. Mean serum bilirubin was significantly elevated (12.7 +/- 8.9 mg/dl) in the experimental group and following relief of biliary obstruction significantly dropped below 1 mg/dl in all animals except one. Concomitant changes in alkaline phosphatase, glutamate oxaloacetate transaminase, and glutamate pyruvate transaminase were seen. Experimental and control rats initially lost weight following laparotomy; however, mean body weight stabilized by the 5th postoperative day and was similar in both groups on the 10th postoperative day. This combined procedure is a simple, effective and reproducible method of obstructive jaundice.