Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury.
Recently, we generated mice lacking microsomal triglyceride transfer protein (MTP) in the liver (Mttp(Delta/Delta)) 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 Mttp(Delta/Delta) livers to additional hepatic insults. To address this issue, we compared the susceptibility of Mttp(Delta/Delta) mice and Mttp(flox/flox) controls to hepatic injury from Escherichia coli lipopolysaccharides, concanavalin A, and Pseudomonas aeruginosa exotoxin A. At baseline, neither the Mttp(Delta/Delta) nor the Mttp(flox/flox) mice had elevated serum transaminases or histologic evidence of hepatic inflammation. After the administration of the toxins, however, the Mttp(Delta/Delta) mice manifested higher levels of transaminases and, unlike the Mttp(flox/flox) mice, developed histologic evidence of hepatic inflammation. The toxic challenge induced tumor necrosis factor-alpha to a similar extent in Mttp(Delta/Delta) and Mttp(flox/flox) mice, but other parameters of injury (e.g. chemokine transcript levels and lipid peroxides) were disproportionately increased in the Mttp(Delta/Delta) mice. Our results suggest that blocking lipoprotein secretion in the liver may increase the susceptibility of the liver to certain toxic challenges.
Björkegren
Johan
J
Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, University of California, San Francisco 94110, USA.
Beigneux
Anne
A
Bergo
Martin O
MO
Maher
Jacquelyn J
JJ
Young
Stephen G
SG
D036002:ADP Ribose Transferases; D000410:Alanine Transaminase / Q000097:blood; D000483:Alleles; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001427:Bacterial Toxins; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000378:metabolism; D005098:Exotoxins / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008099:Liver / Q000293:injuries* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001427:Bacterial Toxins; D001786:Blood Glucose; D003208:Concanavalin A; D016207:Cytokines; D005098:Exotoxins; D007770:L-Lactate Dehydrogenase; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A