Inhibition of hepatic stellate cell collagen synthesis by N-(methylamino)isobutyric acid.
The increased deposition of extracellular matrix by hepatic stellate cells following liver injury, in a process known as activation, is considered a key mechanism for increased collagen content of liver during the development of liver fibrosis. We report that N-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of System A-mediated amino acid uptake, reduces the accumulation of collagen in CFSC-2G hepatic stellate cell cultures and in a rat model of liver injury and fibrosis. Rat CFSC-2G cells were cultured in 0-5mM MeAIB, and the accumulation and synthesis of collagen were measured by binding to Sirius red F3B and pulse-labeling with [3H]-proline, respectively. The effect of MeAIB on collagen accumulation in vivo was evaluated utilizing a rat model of hepatic fibrosis. MeAIB inhibited collagen accumulation in CFSC-2G cultures in a concentration-dependent manner with 5mM MeAIB reducing collagen 44.6+/-1.2% compared with the control. In CFSC-2G cultures, MeAIB selectively inhibited the incorporation of proline into cellular macromolecules by 43+/-4%, while the synthesis of proteins containing leucine was not affected. In vivo, oral administration of 160mg MeAIB/kg body weight per day to rats significantly reduced the hepatic collagen accumulation in response to 1 week of CCl(4)-induced liver injury. MeAIB reduces the accumulation of collagen in CFSC-2G hepatic stellate cell cultures and in a CCl(4)-induced rat model of liver injury and fibrosis.
Freeman
Thomas L
TL
Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, USA. tlfreeman@unmc.edu
Kharbanda
Kusum K
KK
Tuma
Dean J
DJ
Mailliard
Mark E
ME
D000199:Actins / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000621:Aminoisobutyric Acids / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D051381:Rats; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000378:metabolism
D000199:Actins; D000596:Amino Acids; D000621:Aminoisobutyric Acids; D024042:Collagen Type I; C017911:2-(methylamino)isobutyric acid; D011392:Proline; D007930:Leucine