3,4-dihydroxytoluene, a metabolite of rutin, suppresses the progression of nonalcoholic fatty liver disease in mice by inhibiting p300 histone acetyltransferase activity

Jangho Lee1, Ji-Hye Song2, Min-Yu Chung1, Jin-Hyuk Lee3,4, Tae-Gyu Nam5, Jae Ho Park1, Jin-Taek Hwang1,6, Hyo-Kyoung Choi1
1 Korea Food Research Institute, Jeollabuk-do 55365, Republic of Korea
2 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
3 Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
4 Department of Bioinformatics, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
5 Major of Food Science and Biotechnology, Division of Bio-convergence, Kyonggi University, Suwon 16227, Republic of Korea
6 Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
Correspondence to: Jin-Taek Hwang:, Hyo-Kyoung Choi:,
DOI: 10.1038/s41401-020-00571-7
Received: 24 August 2020
Accepted: 2 November 2020
Advance online: 10 December 2020


3,3′,4′,5,7-Pentahydroxyflavone-3-rhamnoglucoside (rutin) is a flavonoid with a wide range of pharmacological activities. Dietary rutin is hardly absorbed because the microflora in the large intestine metabolize rutin into a variety of compounds including quercetin and phenol derivatives such as 3,4-dihydroxyphenolacetic acid (DHPAA), 3,4-dihydroxytoluene (DHT), 3,4- hydroxyphenylacetic acid (HPAA) and homovanillic acid (HVA). We examined the potential of rutin and its metabolites as novel histone acetyltransferase (HAT) inhibitors. DHPAA, HPAA and DHT at the concentration of 25 μM significantly inhibited in vitro HAT activity with DHT having the strongest inhibitory activity. Furthermore, DHT was shown to be a highly efficient inhibitor of p300 HAT activity, which corresponded with its high degree of inhibition on intracellular lipid accumulation in HepG2 cells. Docking simulation revealed that DHT was bound to the p300 catalytic pocket, bromodomain. Drug affinity responsive target stability (DARTS) analysis further supported the possibility of direct binding between DHT and p300. In HepG2 cells, DHT concentration- dependently abrogated p300-histone binding and induced hypoacetylation of histone subunits H3K9, H3K36, H4K8 and H4K16, eventually leading to the downregulation of lipogenesis-related genes and attenuating lipid accumulation. In ob/ob mice, administration of DHT (10, 20 mg/kg, iv, every other day for 6 weeks) dose-dependently improved the NAFLD pathogenic features including body weight, liver mass, fat mass, lipid accumulation in the liver, and biochemical blood parameters, accompanied by the decreased mRNA expression of lipogenic genes in the liver. Our results demonstrate that DHT, a novel p300 histone acetyltransferase inhibitor, may be a potential preventive or therapeutic agent for NAFLD.
Keywords: non-alcoholic fatty liver disease; rutin metabolites; 3 4-dihydroxytoluene; p300 histone acetyltransferase; epigenetic regulation; OPA-induced NAFLD model; ob/ob mice

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