Aldehyde Dehydrogenase-2 as a Drug Target for Cholestatic Liver Fibrosis

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): Fibrotic transformation of the liver is a major cause of death worldwide. The generation of reactive oxygen species (ROS) is a typical feature of chronic liver disease, causing protein damage and lipid peroxidation and leading to formation of toxic aldehydes. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) detoxifies these aldehydes. My recent pilot study showed that Alda-1, a novel small-molecule activator of ALDH2, decreased fibrosis after bile duct ligation (BDL). Accordingly, I seek to validate ALDH2 as a drug target to decrease fibrosis by detoxification of toxic aldehydes. I hypothesize that activation of ALDH2 aids in the detoxification of aldehydes and decreases activation of hepatic stellate cells, thereby suppressing fibrosis and promoting recovery. Success of this study will identify a novel therapeutic target against fibrosis for development of much needed antifibrotic drugs to treat hepatic fibrosis/cirrhosis. I will test this hypothesis through two Specific Aims. 1) Elucidate the anti-fibrotic role of ALDH2 in a mouse model of cholestatic injury. The role of toxic aldehydes in fibrosis remains unclear. Therefore, I will explore whether toxic aldehydes play a critical role in liver fibrosis and if ALDH2 activation attenuates fibrosis after BDL. I will assess time- dependent changes of toxic aldehydes generation (4-hydroxynonenal [4-HNE] and malondialdehyde [MDA]), ALDH2 expression/activity, and fibrotic markers and signals (e.g., alpha-smooth muscle actin [?-SMA], TGF?- 1, PDGF, Smad 2/3, ERK, and NF-?B p65 subunit), and epigenetic control by microRNAs. I will directly image HSC activation and procollagen deposition using intravital multiphoton/second harmonic generation (SHG) microscopy. Fibrotic liver injury is a complex, multicellular process, so I will also determine the effect of ALDH2 activation and deficiency on hepatocellular injury (necrosis and apoptosis) and inflammation after BDL. I expect that ALDH2-deficiency will increase toxic aldehydes and exacerbate hepatic injury and fibrotic activation, whereas ALDH2 activation will mitigate these adverse events. I expect that these studies will validate ALDH2 as a new drug target against ROS-associated liver fibrosis. 2) Determine whether ALDH2 activation inhibits activation of hepatic stellate cells (HSC) and/or causes reversion of activated HSCs to a quiescent state. In addition to my pilot study, previous studies show that aldehydes activate cultured HSCs. I will assess whether ALDH2 activation in HSCs prevents/decreases activation by both exogenous and endogenous aldehydes at early stages and promotes reversion of activated HSCs at later stages. I will verify through ALDH2 knockdown that the effect of Alda-1 is ALDH2 dependent. I expect: 1) Toxic aldehydes will accumulate as HSCs become activated in culture; 2) ALDH2 knockdown will increase, whereas ALDH2 activation by Alda- 1 will delay/decrease spontaneous and exogenous aldehyde-induced HSC activation; and 3) Late administration of Alda-1 will blunt and even reverse HSC activation. These data serve to demonstrate a direct relationship between aldehyde metabolism and activation of HSCs, the primary fibrotic effector cells.