Metabolic Syndrome Ameliorated by 4-Methylesculetin by Reducing Hepatic Lipid Accumulation

Abstract

Obesity is a chronic metabolic disease caused by an imbalance between energy intake and expenditure during a long period and is characterized by adipose tissue disfunction and hepatic steatosis. The aim of this study was to investigate the effect of 4-methylesculetin (4-ME), a coumarin derivative, upon adipose microenvironment and hepatic steatosis in mice induced by a high-fat diet (HFD), and to explore potential mechanisms of its beneficial effect on metabolic disorders. HFD-fed mice displayed visceral obesity, insulin resistance, and hepatic lipid accumulation, which was remarkably ameliorated by 4-ME treatment. Meanwhile, 4-ME ameliorated adipocyte hypertrophy, macrophage infiltration, hypoxia, and fibrosis in epididymal adipose tissue, thus improving the adipose tissue microenvironment. Furthermore, 4-ME reversed the increase in CD36, PPAR-γ, SREBP-1, and FASN, and the decrease in CPT-1A, PPAR-α, and Nrf2 translocation into the nucleus in livers of HFD mice and in FFA-incubated hepatocytes. Moreover, the beneficial effects of 4-ME upon lipid deposition and the expression of proteins related to lipid metabolism in FFA-induced LO2 cells were abolished by ML385, a specific Nrf2 inhibitor, indicating that Nrf2 is necessary for 4-ME to reduce hepatic lipid deposition. These findings suggested that 4-ME might be a potential lead compound candidate for preventing obesity and MAFLD.

Natural Coumarin Derivatives Activating Nrf2 Signaling Pathway as Lead Compounds for the Design and Synthesis of Intestinal Anti-Inflammatory Drugs

“…The activation of the Nrf2 signaling pathway was also reported as a key action for 4-methylesculetin to induce a reduction of body weight, visceral obesity, blood glucose, adipocyte size, and hepatic lipid accumulation, after oral treatment with 15 and 50/Kg by 8 weeks in obese mice by a high-fat diet [74]. Similar to other simple coumarins, the antiinflammatory effects of esculin were closely related to the Nrf2 activation and subsequent upregulation of HO-1 and NQO1 expression [75].…”

ATL I, Acts as a SIRT6 Activator to Alleviate Hepatic Steatosis in Mice via Suppression of NLRP3 Inflammasome Formation

“…Atractylenolide III activates the hepatic adiponectin receptor 1 (AdipoR1)/AMPK axis to ameliorate non-alcoholic fatty liver disease [28]. 4-Methylesculetin increases CPT-1A, PPARα, and nuclear factor erythroid 2-related factor 2 Nrf2, while decreased CD36, PPAR-γ, SREBP-1, and fatty acid synthase (FASN) reduce hepatic lipid accumulation [29]. Lactucin and lactucopicrin target trifunctional enzyme subunit alpha (HADHA), disintegrin, metalloproteinase domain-containing protein 17 (ADAM17), Sequestosome-1 (SQSTM1), and lysosomal acid glucosylceramidase (GBA) genes to promote fatty acid oxidation, and then ameliorate FFA-induced steatosis [30].…”

Multimodal Strategies to Fight Obesity: Research on Tailored Therapies Based on Natural and Synthetic Compounds for Prevention, Management and Treatment

“…A beneficial effect against HFD-induced lipotoxicity also seems to be also exerted by 4-methylesculetin (6,7-dihydroxy-4-methylcoumarin, 4-ME), a coumarin derivative isolated from Artemisia annua [ 35 ]. Li et al showed that 4-ME treatment attenuated adipocyte hypertrophy, macrophage infiltration, hypoxia and fibrosis in epididymal adipose tissue in HFD-fed mice, thus improving the adipose tissue microenvironment.…”

“…These effects are correlated with the ability of 4-ME to down-regulate CD36; the free FA cell-surface receptor; as well as SREBP-1, PPAR-γ and FASN protein, transcription factors and enzymes that are involved in lipogenesis. Furthermore, 4-ME activated Nrf2, an important antioxidant transcriptional factor that can also indirectly suppress the expression of SREBP-1 and its lipogenic target genes [ 35 ].…”