Research Project
10052866
PROJECT SUMMARY / ABSTRACT Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality in the United States and worldwide. Unfortunately, there is currently no FDA approved medication for any stage of ALD. Advancing our knowledge on the pathophysiologic mechanisms of ALD will certainly pave the way to development of therapeutic interventions. One of the known mechanisms of alcohol-induced liver injury is the perturbation of lipid metabolic pathways. In fact, alcoholic steatosis is the earliest pathological change in ALD. In the past funding period, we have shown that instead of triglyceride, accumulated free fatty acid (FFA) levels positively correct with disease severity in experimental models of ALD. However, how alcohol causes FFA accumulation in the liver and the feasibility of FFA lowering approaches for treating ALD are still open questions to be elucidated. Through profiling hepatic FFAs, we found that the most significantly altered and abundant FFA species were long chain FAs (LCFA) which were increased by alcohol. On the other hand, their activated forms, long chain acyl-CoAs, were decreased by alcohol, suggesting a defect in FA activation by long chain acyl-CoA synthetase (ACSL). Our preliminary study detected two ACSL isoforms in the liver, ACSL1 and ACSL4, that both were downregulated after alcohol exposure. ACSL1 is a major form of hepatic ACSLs that is critical for channeling FA to mitochondrial ?-oxidation, whereas ACSL4 specifically targets arachidonic acid (AA) metabolism and has been reported to be critically involved in ER VLDL lipidation. Along with reduced VLDL secretion rate as well as its lipidation status, we indeed found that alcohol exposure decreases hepatic AA-CoA despite an increased AA. Moreover, we found that the expression of ACSL1 and ACSL4 were positively correlated with aryl hydrocarbon receptor both in vivo and in vitro. All evidence collected strongly supports a novel concept that defect in ACSL-mediated hepatic FA channeling plays a critical role in FA disposal disorder and in alcohol-induced lipotoxicity, which is tightly controlled by AhR. We will test the hypothesis in 3 aims. In Aim 1, we will investigate the role of ACSL1 in directing the metabolic switch toward mitochondrial ?-oxidation versus ER ?-oxidation in order to reduce toxic lipid production from ER and to prevent lipotoxicity in ALD. In Aim 2, we will explore how ACSL4 is involved in AA channeling to ER for VLDL lipidation and/or to peroxisome for ?-oxidation other than converting to toxic lipid mediators. In Aim 3, we will determine whether the expression of ACSL is regulated by AhR at transcription level. We also will test the effect of endogenous AhR ligand in reversing ACSL expression and protecting alcohol- induced lipotoxicity. Understanding these mechanisms will enable us to develop targeted dietary therapies to prevent and treat ALD.
