The suckling rat has provided a useful model for these studies of lipid digestion and absorption. In adults dietary triacylglycerols are predominantly hydrolyzed by the "classic" mechanism involving pancreatic lipase (E.C. 3.1.1.3) and biliary micelle-mediated product uptake. Unlike affluent man, adult laboratory rats normally consume a low-fat diet (< 20% of energy). However suckling rats, like most neonates, consume a milk diet that is normally high in fat. Suckling rats receive ~90% of non-protein energy from milk triacylglycerols, although rats have very low levels of "classic" pancreatic lipase before weaning. Dissertation studies demonstrate that other lipases promote efficient gastrointestinal triacylglycerol utilization in suckling rats. Nearly half of milk triacylglycerols are hydrolyzed to diacylglycerol within the stomach; and results strongly support that lingual lipase is the significant source of this activity. Furthermore, enzyme studies show considerable similarity between this lipase from rat tongue and so-called pregastric esterases of suckling ruminant species. Of fatty acids released in stomach, nearly three-quarters are of medium-chain length. These have high aqueous solubility and are rapidly absorbed from the upper gastrointestinal tract. Remaining triacylglycerols, diacylglycerols, and long-chain fatty acids enter the intestinal lumen and mix with lipid-rich bile. Suckling rats have higher biliary concentrations of bile salts, phospholipids and cholesterol than do adults. Bile salt enterohepatic circulation clearly occurs in the suckling rat, at least as early as 10 days. The bile acid β-muricholate is elevated during the suckling period, compared to post-weaning. Results show that further lipolysis occurs along the intestine, possibly through the action of lingual lipase and others from pancreas, producing mostly long-chain free fatty acids, monoacylglycerol, and some lysophosphatidylcholine, derived largely from bile. This composition closely resembles adult intestinal contents, but is much higher in both dietary and biliary lipid constituents. Alteration of milk triacylglycerol fatty acids produced no apparent impairment in gastrointestinal lipid utilization by sucklings, but resulted in hyperlipemia and increased carcass fatness. These results suggest gastrointestinal events do not limit triacylglycerol utilization in the suckling rat, regardless of composition; but post-absorptive metabolism may be different when sucklings consume altered milk lipids.

This investigation was concerned with characterizing effects of this tumor line on lipid metabolism in DBA/lJ mice and serum protein levels and cellular changes in DBA/lJ and Swiss white mice. Total lipids, lipid phosphorus, neutral lipids, and changes in fatty acids were determined in liver, spleen, skin, and tumor of DBA/lJ mice bearing the lymphosarcoma at various days after injection of tumor cells.

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Bioactivation of organohalogen xenobiotics produces reactive intermediates which alkylate macromolecules. The activation of carbon tetrachloride, trichloroethylene, and methylene chloride was studied in isolated rat hepatocytes by examining alkylation of lipid, protein, RNA, and DNA. All organohalogens alkylated lipid and protein. Carbon tetrachloride and trichloroethylene, but not methylene chloride, alkylated RNA and DNA. Methylene chloride was more highly activated in an oxygen containing atmosphere by hepatocytes, consistent with a proposed formation of formyl chloride as its reactive intermediate. Trichloroethylene was also shown to be more highly activated in an oxygen containing atmosphere, consistent with a proposed trichloroethylene epoxide reactive intermediate. Carbon tetrachloride was shown to be more highly activated in an oxygen-free atmosphere, consistent with a proposed trichloromethyl free radical reactive intermediate. Hepatocytes from rats pretreated with phenobarbital to induce cytochrome P-450 mixed function oxidase activated carbon tetrachloride and trichloroethylene to alkylating intermediates greater than did hepatocytes from non-induced rats. The interaction of carbon tetrachloride metabolites with fatty acids was studied in a chemical activation model system. The thermal decomposition of benzoyl peroxide produced free radicals which activated carbon tetrachloride. The resulting trichloromethyl free radicals abstracted a hydrogen from methyl stearate resulting in chloroform and fatty acid free radicals. Using chemical ionization mass spectrometry, it was discovered that the fatty acid free radical abstracted a chlorine from carbon tetrachloride resulting in chlorinated fatty acid esters. When methyl oleate was used as a substrate in the benzoyl peroxide model system, it was discovered that the trichloromethyl free radical binds covalently, resulting in a fatty acid adduct radical. This radical then abstracted a chlorine to produce chloro, trichloromethyl stearic acid methyl ester, identified by chemical ionization mass spectrometry. Carbon tetrachloride radiolabeled with ¹⁴C or ³⁶Cl in dual label binding experiments in the benzoyl peroxide model system confirmed the mass spectral data. Methyl stearate bound ³⁶Cl- and ¹⁴C-carbon tetrachloride in the ratio of approximately 10 to 1, whereas methyl oleate bound in the ratio of approximately 3.5 to 1. The existence of fatty acid radicals due to hydrogen abstraction or covalent binding by trichloromethyl free radicals was demonstrated in microsomal preparations. In the presence of tritiated water and ¹⁴C-carbon tetrachloride, dual-label analysis demonstrated that the tritium incorporation into microsomal lipids approximately equalled the sum of carbon tetrachloride metabolites bound covalently to microsomal lipids and chloroform production.

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Mutations in the clk-1 gene of Caenorhabditis elegans result in an average slowing down and deregulation of a variety of developmental and physiological processes. In addition, clk-1 mutants are defective in responding to temperature changes. For example, wild-type worms adjust their defecation cycle length after a temperature shift whereas the defecation cycle length of clk-1 mutants is unaffected by such a shift. To understand the basis of the clk-1 phenotype, a number of genetic screens have been carried out to isolate feature-specific suppressor mutations. dsc-3(qm179) and dsc-4(qm182) were isolated in this manner. It has previously been found that dsc-3(qm179) and dsc-4(qm182) strongly suppress the slow defecation phenotype of clk-1 mutants at 20°C, as well as after a temperature shift to 25°C. Molecular analysis of dsc-4, which encodes the microsomal triglyceride transfer protein, suggests that dsc genes affect lipid metabolism. We carried out a genetic screen for additional mutations that can suppress the slow defecation of clk-1 mutants after a temperature shift to 25°C and isolated two new suppressor mutations. Complementation tests as well as linkage analysis and mapping indicates that dsc-6(qm192) and dsc-7(qm193) define new dsc genes. We analyzed the phenotype of the new suppressor strains and have found that, like dsc-4(qm182), dsc-6(qm192) and dsc-7(qm193) can suppress a variety of clk-1 phenotypes. Based on additional phenotypic analyses of the new suppressor strains, including the determination of their sensitivity to exogenous cholesterol, we believe that, like dsc-4, dsc-6 and dsc-7 encode activities that affect lipid metabolism in worms.