Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury

Johan Björkegren, Anne Beigneux, Martin O. Bergo, Jacquelyn J. Maher, Stephen G. Young

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Recently, we generated mice lacking microsomal triglyceride transfer protein (MTP) in the liver (MttpΔ/Δ) and demonstrated that very low density lipoprotein secretion from hepatocytes was almost completely blocked. The blockade in lipoprotein production was accompanied by mild to moderate hepatic steatosis, but the mice appeared healthy. Although hepatic MTP deficiency appeared to be innocuous, we hypothesized that a blockade in very low density lipoprotein secretion and the accompanying steatosis might increase the sensitivity of MttpΔ/Δ livers to additional hepatic insults. To address this issue, we compared the susceptibility of MttpΔ/Δ mice and Mttpflox/flox controls to hepatic injury from Escherichia coli lipopolysaccharides, concanavalin A, and Pseudomonas aeruginosa exotoxin A. At baseline, neither the MttpΔ/Δ nor the Mttpflox/flox mice had elevated serum transaminases or histologic evidence of hepatic inflammation. After the administration of the toxins, however, the MttpΔ/Δ mice manifested higher levels of transaminases and, unlike the Mttpflox/flox mice, developed histologic evidence of hepatic inflammation. The toxic challenge induced tumor necrosis factor-α to a similar extent in MttpΔ/Δ and Mttpflox/flox mice, but other parameters of injury (e.g. chemokine transcript levels and lipid peroxides) were disproportionately increased in the MttpΔ/Δ mice. Our results suggest that blocking lipoprotein secretion in the liver may increase the susceptibility of the liver to certain toxic challenges.

Original languageEnglish
Pages (from-to)5476-5483
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number7
DOIs
StatePublished - 15 Feb 2002
Externally publishedYes

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