Inhibition of hepatic gluconeogenesis and lipogenesis by benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459

Sylvia A. McCune, Pamela J. Durant, Lloyd E. Flanders, Robert Harris

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459 were found to inhibit glucose synthesis by hepatocytes isolated from 48-h fasted rats as well as fatty acid synthesis by hepatocytes isolated from meal-fed rats. Glucose synthesis was less sensitive than fatty acid synthesis. Benzoic acid was the least effective inhibitor of both processes; SC-33459 and p-tert.-butylbenzoic acid were very potent inhibitors with similar efficacy. Glycine prevented the inhibition of fatty acid synthesis caused by benzoic acid, but had no effect on that caused by p-tert.-butylbenzoic acid. Octanoate opposed the inhibitory effects of both benzoic acid and p-tert.-butylbenzoic acid. Oxidation of [1-14C]oleate to ketone bodies and acid-soluble radioactive products was inhibited by both p-tert.-butylbenzoic acid and SC-33459. Preincubation of hepatocytes with SC-33459 was required for the latter effect, suggesting catabolism of this compound may be involved. SC-33459 is a p-tert.-butylphenyl derivative which should be readily converted to p-tert.-butylbenzoic acid by β oxidation. Both p-tert.-butylbenzoic acid and SC-33459 decreased citrate levels dramatically. All three compounds reduced CoA and acetyl-CoA levels and increased medium-chain acyl-CoA ester levels. p-tert.-Butylbenzoic acid and SC-33459 also increased long-chain acyl-CoA ester levels. The increase in medium-chain acyl-CoA levels presumably reflects benzoyl-CoA formation from benzoic acid and p-tert.-butylbenzoyl-CoA formation from p-tert.-butylbenzoic acid and SC-33459. Inhibition of glucose and fatty acid synthesis by these compounds may be due to effects on specific enzymes or to CoA sequestration.

Original languageEnglish
Pages (from-to)124-133
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume214
Issue number1
DOIs
StatePublished - 1982

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Hypolipidemic Agents
Lipogenesis
Benzoic Acid
Gluconeogenesis
Acids
Liver
Acyl Coenzyme A
Fatty Acids
Coenzyme A
Hepatocytes
Glucose
Rats
Esters
SC 33459
Ketone Bodies
Oxidation
Acetyl Coenzyme A
Oleic Acid
Citric Acid
Glycine

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Inhibition of hepatic gluconeogenesis and lipogenesis by benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459. / McCune, Sylvia A.; Durant, Pamela J.; Flanders, Lloyd E.; Harris, Robert.

In: Archives of Biochemistry and Biophysics, Vol. 214, No. 1, 1982, p. 124-133.

Research output: Contribution to journalArticle

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abstract = "Benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459 were found to inhibit glucose synthesis by hepatocytes isolated from 48-h fasted rats as well as fatty acid synthesis by hepatocytes isolated from meal-fed rats. Glucose synthesis was less sensitive than fatty acid synthesis. Benzoic acid was the least effective inhibitor of both processes; SC-33459 and p-tert.-butylbenzoic acid were very potent inhibitors with similar efficacy. Glycine prevented the inhibition of fatty acid synthesis caused by benzoic acid, but had no effect on that caused by p-tert.-butylbenzoic acid. Octanoate opposed the inhibitory effects of both benzoic acid and p-tert.-butylbenzoic acid. Oxidation of [1-14C]oleate to ketone bodies and acid-soluble radioactive products was inhibited by both p-tert.-butylbenzoic acid and SC-33459. Preincubation of hepatocytes with SC-33459 was required for the latter effect, suggesting catabolism of this compound may be involved. SC-33459 is a p-tert.-butylphenyl derivative which should be readily converted to p-tert.-butylbenzoic acid by β oxidation. Both p-tert.-butylbenzoic acid and SC-33459 decreased citrate levels dramatically. All three compounds reduced CoA and acetyl-CoA levels and increased medium-chain acyl-CoA ester levels. p-tert.-Butylbenzoic acid and SC-33459 also increased long-chain acyl-CoA ester levels. The increase in medium-chain acyl-CoA levels presumably reflects benzoyl-CoA formation from benzoic acid and p-tert.-butylbenzoyl-CoA formation from p-tert.-butylbenzoic acid and SC-33459. Inhibition of glucose and fatty acid synthesis by these compounds may be due to effects on specific enzymes or to CoA sequestration.",
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