title: Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.
abstract: Tumor necrosis factor (TNF) induces hyperlipidemia in rodents by increasing hepatic triglyceride production. We now explore the mechanism of this increase. TNF does not increase phosphatidate phosphohydrolase, glycerolphosphate acyltransferase, or diacylglycerol acyltransferase, which are enzymes of triglyceride synthesis. Rather, TNF increases triglyceride production by providing increased fatty acids (FA) as substrate. In chow-fed rats, TNF increases plasma free fatty acids (FFA). The antilipolytic drug, phenylisopropyl adenosine (PIA), prevents the TNF-induced increase in plasma FFA and, most importantly, inhibits the TNF-induced increase in plasma triglycerides. Thus increased lipolysis with delivery of FA to liver contributes to TNF-induced hyperlipidemia in chow-fed animals. In contrast, in rats fed a high-sucrose diet, TNF causes hyperlipidemia without increasing plasma FFA, and PIA has no effect on TNF-induced increases in plasma triglycerides. However, in sucrose-fed rats, TNF markedly stimulates hepatic de novo FA synthesis, which provides FA. This diet determines the mechanism by which TNF stimulates hepatic triglyceride production. The use of multiple mechanisms to increase plasma triglycerides suggests that this TNF action plays an important role in the response to infection or inflammation.
authors.affiliation: Department of Medicine, University of California, San Francisco, California.
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
authors.forename: S
authors.initials: S
authors.lastname: Adi
authors.forename: I
authors.initials: I
authors.lastname: Staprans
authors.forename: A H
authors.initials: AH
authors.lastname: Moser
authors.forename: R
authors.initials: R
authors.lastname: Neese
authors.forename: J A
authors.initials: JA
authors.lastname: Verdier
authors.forename: W
authors.initials: W
authors.lastname: Doerrler
authors.forename: C
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D002914:Chylomicrons / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D051048:Diacylglycerol O-Acyltransferase; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005990:Glycerol / Q000097:blood; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D014280:Triglycerides / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002914:Chylomicrons; D005230:Fatty Acids, Nonesterified; D011994:Recombinant Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D010660:Phenylisopropyladenosine; D000217:Acyltransferases; D005992:Glycerol-3-Phosphate O-Acyltransferase; D051048:Diacylglycerol O-Acyltransferase; D010711:Phosphatidate Phosphatase; D005990:Glycerol