Grant Abstract: Nutritional transcriptomics approach for the role of astaxanthin in liver fibrosis

Grant Number: 5R01DK108254-04
PI Name: Lee
Project Title: Nutritional transcriptomics approach for the role of astaxanthin in liver fibrosis

Abstract: The objectives of parent grant (1R01DK108254-03, 9/25/2015-8/31/2019) are to conduct a genome-wide transcriptome analysis to identify new histone deacetylase 9 (HDAC9)-regulated genes by which the antifibrogenic effect of astaxanthin (ASTX), a carotenoid, is mediated in hepatic stellate cells (HSC). Nicotinamide riboside (NR) is a vitamin B3 and naturally present in cow’s milk and beer. As a bioavailable NAD+ precursor, NR exerts its biological effect by activating sirtiuns, many of which are known to have health benefits. We previously demonstrated that NR supplement prevents the development of nonalcoholic fatty liver disease (NAFLD) in a diet-induced obesity mouse model. However, whether NR can inhibit the development of liver fibrosis in a well-established mouse model of diet-induced liver fibrosis has yet to be determined. In addition, potential mechanisms of action by which NR prevents liver fibrosis in obesity have not been elucidated. In the supplemental project, we will test hypothesis that NR exerts an anti-fibrotic action in the liver by preventing hepatic stellate cell (HSC) activation while facilitating the inactivation of activated HSC. This, in turn, prevents the development of liver fibrosis. In Specific aim 1, we will determine the effect of NR on HSC activation in vitro; and test whether genes/pathways identified by the parent grant are also critically involved in the HSC activation process altered by NR treatment. In Specific aim 2, we will evaluate whether consumption of NR supplement can prevent the development of liver fibrosis in a diet-induced liver fibrosis mouse model; and validate the findings, i.e., gene signatures critically involved in liver fibrosis, from the parent grant in vivo. This proposed study is unique from the parent grant in that it will test a potential role of NR in HSC activation/inactivation and liver fibrosis as a new dietary supplement. Also, we will determine whether NR supplementation can alter metabolic rate, physical activity, and eating behaviors in vivo using a newly established CLAMS in our lab. The results will add new insight into potential mechanisms for the benefit of NR consumption in the prevention of obesity associated disease including NAFLD; and they may guide us to a new direction for future investigation to elucidate underlying mechanisms for the effect of NR. In our parent grant, we have identified gene signatures/pathways involved in HSC activation and liver fibrosis that are sensitive to ASTX and HDAC9. It is a critical question whether the genes and pathways are sensitive only to ASTX or are common targets of antifibrotic agents. If ASTX and NR exert their anti-fibrotic action by different mechanisms, future study is warranted to test whether supplementation of ASTX and NR in combination could have a synergistic or an additive benefit for the prevention of liver fibrosis. If ASTX and NR share the same mechanisms to prevent liver fibrosis, this supplemental project will validate findings of the parent grant. Additionally, by comparing the efficacy of ASTX in the prevention of liver fibrosis with that of NR, better preventive strategy against liver fibrosis can be established.

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