Inhibition of hepatic stellate cell collagen synthesis by N-(methylamino)isobutyric acid

• Published in: Biochemical pharmacology 2002-02, Vol.63 (4), p.697-706
• Main Authors: Freeman, Thomas L., Kharbanda, Kusum K., Tuma, Dean J., Mailliard, Mark E.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Amino Acids - pharmacology; Aminoisobutyric Acids - pharmacology; Animals; Biological and medical sciences; Cells, Cultured; Chemical and industrial products toxicology. Toxic occupational diseases; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Gene Expression - drug effects; Hepatic stellate cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Leucine - metabolism; Liver Cirrhosis - metabolism; Liver fibrosis; Medical sciences; N-(Methylamino)isobutyric acid; Proline - metabolism; Rats; Respiratory Distress Syndrome, Adult - enzymology; Respiratory Distress Syndrome, Adult - metabolism; Solvents; Toxicology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00885-1

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 0–5 mM MeAIB, and the accumulation and synthesis of collagen were measured by binding to Sirius red F3B and pulse-labeling with [ 3 H ]-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 5 mM 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 160 mg 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.