Activation of Kupffer cells by gut-derived
endotoxin is an important factor in
ethanol hepatotoxicity. Further, it was shown that
ethanol modulates both the expression and activity of several intracellular signaling molecules and
transcription factors in Kupffer cells and chronic
ethanol treatment enhances Kupffer cell sensitivity to
endotoxin. These findings suggest that inhibition of Kupffer cell activation is effective for clinical application in
alcoholic hepatitis. Recently, accumulating lines of evidence suggest a possibility that
glycine is useful as an immuno-modulating
amino acid. It has been shown that a diet containing
glycine improved survival in
endotoxin shock by preventing Kupffer cell activation.
Glycine most likely prevents the LPS-induced elevation of intracellular Ca concentration in Kupffer cells, thereby minimizing
LPS receptor signaling and
cytokine production. Indeed,
glycine prevents alcohol-induced liver injury in a long-term enteral
ethanol feeding rats (Tsukamoto-French) by decreasing production of
TNF-alpha in the liver. Moreover,
glycine is protective against apoptosis of sinusoidal endothelial cells (SECs) that is one of the initial events in the development of liver injury. On the other hand, epidemiologic data have identified chronic alcohol consumption as a significant risk factor for
carcinogenesis. Interestingly,
glycine inhibits growth of
tumor in vivo most likely because of the inhibition of angiogenesis. It was shown that the inhibitory effect of
glycine on growth and migration of endothelial cells is due to activation of a
glycine-gated Cl channel. It is hypothesized that the opening of this
anion channel hyperpolarizes the cell membrane, blocks influx of Ca through voltage-dependent Ca channel, thereby blunting
growth factor-mediated signaling. Therefore,
glycine can be used not only for treatment of
alcoholic hepatitis, but also for
chemoprevention and treatment of
hepatocellular carcinoma in
alcoholic cirrhosis. Taken together, it is concluded that
glycine is a potent therapeutic immuno-nutrient for various kinds of chronic
liver diseases including
alcoholic liver disease (ALD).