Rabbit liver apolipoprotein A-I synthesis is under nonparenchymal cell paracrine control.
Apolipoprotein A-I (apoA-I), the primary protein of high density lipoprotein, originates from intestine and liver of almost all mammalian species. In contrast to most species, intact rabbit liver is only capable of producing minute amounts of apoA-I mRNA and protein. In this report we demonstrate that purified rabbit hepatic parenchymal cells have apoA-I mRNA levels approximately 50-fold higher than intact liver after 48 h in monolayer culture. Investigations of the differential between in vivo and in vitro expression showed that conditioned media from nonparenchymal cells, a cell population essentially absent in parenchymal cell cultures, inhibited the elevation of apoA-I mRNA in a specific, concentration-dependent, and reversible fashion. Furthermore, at a concentration of nonparenchymal cell-conditioned media that inhibited apoA-I mRNA levels by > 80% compared to control, there were only slight changes in apoB, apoE, LDL receptor, LCAT, 7 alpha-hydroxylase, hepatic lipase, HMG-CoA reductase, and albumin mRNA levels. Metabolic labeling of parenchymal cell secreted proteins with [35S]methionine followed by apoA-I immunoprecipitation revealed that apoA-I synthesis and secretion corresponded to the changes observed for apoA-I mRNA. Initial biochemical characterization of the nonparenchymal cell media revealed that the inhibitory factor was > 30 kDa, heat-stable to 70 degrees C, and still active after urea denaturation and renaturation. These data suggest that, in rabbits, hepatic parenchymal-nonparenchymal communication in the form of a secreted factor may attenuate liver apoA-I expression in vivo.
Division of Therapeutics, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, MI 48105.
T J
TJ
Rea
C L
CL
Bisgaier
R B
RB
DeMattos
M E
ME
Pape
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D006728:Hormones / Q000502:physiology*; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits
D016632:Apolipoprotein A-I; D006728:Hormones; D012333:RNA, Messenger