Basic Research

The Center takes a pride in having supported cutting-edge research by the Center investigators that resulted in significant contributions to the understanding of liver and pancreas biology through their investigation on the center's theme. These studies have identified new molecular targets for ALPD and cirrhosis. The following are seven most significant publications that we have selected as examples:

Breakthrough Discoveries

Authors underlined are the Center Investigators.

• Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, Enrich C, Fernandez-Checa JC, Garcia-Ruiz C. Mitochondrial free cholesterol loading sensitizes to TNF and Fas mediated steatohepatitis. Cell Metab 4:185-198, 2006.

Using nutritional and genetic models of hepatic steatosis, this study uncovered a key role of mitochondrial free cholesterol as opposed to free fatty acids or triglycerides in the progression from steatosis to steatohepatitis by sensitizing to inflammatory cytokines-mediated hepatocellular death and inflammation via mitochondrial GSH depletion. This study may provide novel therapeutic avenues for ASH and NASH.

• Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol fed mice.  Gastroenterology 124:1488-1499, 2003.

This is the first recognition of the occurrence of ER stress in ALD and is a landmark observation.  It also confirms the development of alcohol-induced hyperhomocysteinemia a cause of ER stress and fatty liver as prevention of hyperhomocysteinemia with betaine attenuates ER stress, fatty liver, and apoptosis in alcohol-fed mice.

• Yang HP, Iglesias Ara A, Magilnick N, Xia M, Ramani K, Chen H, Lee TD, Mato JM, and Lu SC. Expression pattern, regulation and function of methionine adenosyltransferase 2β alternative splicing variants in hepatoma cells. Gastroenterology in press.

Methionine adenosyltransferase (MAT) is an essential enzyme for being the only enzyme responsible for the biosynthesis of S-adenosylmethionine. MAT2b gene encodes for a regulatory subunit b that modulates the activity of MAT2A-encoded isoenzyme. This work uncovered multiple MAT2b splicing variants (V1 and V2) while characterizing its 5'-flanking region. Both V1 and V2 variants are markedly up-regulated in HCC and may offer growth advantage in liver cancer cells. V1 but not V2 also regulate apoptosis in both liver and colon cancer cells. TNFα selectively induces the expression of only V1, which acts as another NF-κB-dependent survival gene. Reduced expression of V1 leads to JNK activation, apoptosis and sensitizes HepG2 cells to TNFα-induced apoptosis while overexpression of V1 is protective. These are aspects of V1 previously unrecognized and greatly broaden the importance of this gene in biology and ALD.

• Chen L, Xiong S, She H, Lin SW, Wang J, and Tsukamoto H. Iron causes interactions of TAK1, p21ras, and PI3K in caveolae to activate IκB kinase in hepatic macrophages.  J Biol Chem 282:5582-5588, 2007

This study demonstrates that iron serves as an independent agonist to activate IKK and NF-κB in Kupffer cells to promote their pro-inflammatory activation and that this signaling involves protein-protein interactions of TAK1, p21ras, and PI3K in caveolae, a novel upstream signaling event that may serve as a priming mechanism in ALD.

• Han YP, Yan C, Zhou L, Qin L, Tsukamoto, H. An MMP-9 activation cascade by hepatic stellate cells in transdifferentiation in 3D ECM.  J Biol Chem 282:12928-39, 2007.

This work reveals trans-differentiation of hepatic stellate cells exposed to IL-1 in 3D ECM is mediated by MMP-9 activation which is facilitated by activation of MMP-13 which in turn requires MMP-14.  This represents the first demonstration of a cascde of MMP-9 activation involving MMP-14 and MMP13 in stellate cell activation.

• Satoh A, Satoh A, Gukovskaya AS, Reeve JR Jr, Shimosegawa T, Pandol SJ. Ethanol sensitizes NF-kappaB activation in pancreatic acinar cells through effects on protein kinase C-epsilon. Am J Physiol 292:G432-8, 2006.
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This study demonstrates the different modes of activation of PKC isoforms and NF-κB in pancreatic tissue stimulated with ethanol plus low or high-dose CCK-8. The results indicate that activation of both PKC-epsilon and -delta is required for NF-κB activation. They further show that ethanol itself causes activation of PKC-epsilon which underlies sensitization of pancreas for NF-κB activation. This is a breakthrough study that identifies a specific signal responsible for the effects of ethanol on a key pathobiologic response of pancreatitis. 

• Mareninova OA, Sung K-F, Hong P, Lugea A, Pandol SJ, Gukovsky I, Gukovskaya AS. Cell death in pancreatitis: caspases protect from necrotizing pancreatitis. J Biol Chem 281:3370-3381, 2006.

The study investigates the mechanisms mediating acinar cell death in experimental acute pancreatitis, and in particular, the balance between apoptosis and more deleterious necrosis. The results indicate key roles for caspases, XIAP, and RIP in the cell death responses of acute pancreatitis. They show how manipulating death-signaling mechanisms changes the necrosis/apoptosis pattern and the severity of experimental pancreatitis. Caspases, XIAP and RIP represent novel potential therapeutic targets in treatment of pancreatitis, especially to prevent or attenuate necrosing pancreatitis.