TY - JOUR
T1 - Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury
AU - Björkegren, Johan
AU - Beigneux, Anne
AU - Bergo, Martin O.
AU - Maher, Jacquelyn J.
AU - Young, Stephen G.
PY - 2002/2/15
Y1 - 2002/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037085471&partnerID=8YFLogxK
U2 - 10.1074/jbc.M108514200
DO - 10.1074/jbc.M108514200
M3 - Article
C2 - 11739387
AN - SCOPUS:0037085471
SN - 0021-9258
VL - 277
SP - 5476
EP - 5483
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
ER -