TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish s-adenosylhomocysteine hydrolase

INTRODUCTION Hepatic steatosis, the accumulation of lipid within hepatocytes, is a critical step in the pathogenesis of human diseases such as alcoholic liver disease, non-alcoholic fatty liver disease associated with the metabolic syndrome, chronic hepatitis C infection and other disorders. In more severe forms of these conditions, the liver becomes inflamed and fatty liver progresses to non-alcoholic steatohepatitis (NASH). Understanding the factors affecting this progression is vital because steatohepatitis is a risk factor for cirrhosis, liver failure and hepatocellular carcinoma. Several pathogenic mechanisms appear to contribute to the development of hepatic steatosis and steatohepatitis, and it has been proposed that multiple ‘hits’ are required for disease progression. Hepatocytes accumulate lipid when its synthesis, uptake, secretion and/or utilization are altered (Browning and Horton, 2004; Fromenty et al., 2004). Although the events that initiate most steatotic disorders are now beginning to be more clearly defined, it has been recognized for many years that methionine metabolism, which is altered in patients with alcoholic liver disease and other chronic liver disorders associated with steatosis, may play a contributory role (Diehl, 2005; Duong et al., 2006; Esfandiari et al., 2005; Innis and Hasman, 2006; Kharbanda, 2007; Lu et al., 2002; Mato et al., 2008; Wortham et al., 2008; Zhu et al., 2003). Mitochondrial dysfunction, endoplasmic reticulum stress, sensitization to cytokine-induced liver injury and reduced methyltransferase activities have all been implicated in mediating the effects of methionine metabolism defects in the mammalian liver. The recessive lethal zebrafish mutant ducttrip (dtp) was recovered in a screen for exocrine pancreas mutants (Yee et al., 2005). Initial phenotypic analysis showed normal differentiation of early dtp exocrine progenitors, whereas their proliferation, terminal differentiation and survival were disrupted at later stages (Yee et al., 2005). Subsequent experiments, described in this report, reveal hepatic steatosis, mitochondrial dysfunction and liver degeneration in all dtp larvae, as well as a milder phenotype in adult heterozygous dtp carriers. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy), the enzyme that hydrolyzes S-adenosylhomocysteine (SAH) to homocysteine and adenosine, a pathway that has been linked to mitochondrial dysfunction (Song et al., 2007) and hepatic steatosis. These findings argue that a heritable reduction in Ahcy activity may be a predisposing genetic risk factor for hepatic steatosis. Consistent with such a role for AHCY in humans, steatosis and liver injury were reported in hypermethioninemic patients recently shown to carry homozygous AHCY mutations (Baric et al., 2005; Baric et al., 2004; Buist et al., 2006).