Morin, a novel liver X receptor α/β dual antagonist, has potent therapeutic efficacy for nonalcoholic fatty liver diseases

Gu, Ming; Zhang, Yu; Liu, Chuhe; Wang, Dongshan; Li, Feng; Fan, Shengjie; Yang, Baican; Tong, Qingchun; Ji, Guang

doi:10.1111/bph.13933

Cited by 34 publications

(22 citation statements)

References 64 publications

(68 reference statements)

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“…All analyses were performed using GraphPad Prism 6.0 (Graph Pad Software, San Diego, CA, USA; RRID:SCR_002798) or SPSS 19.0 software (IBM, Chicago, IL, USA; RRID:SCR_002865). Sample size of each protocol was determined on the basis of similar previous studies (Gu et al, 2017; Wang et al, 2017). Group size is the number of independent values and that statistical analysis was done using these independent values.…”

Section: Methodsmentioning

confidence: 99%

Cyanidin‐3‐O‐glucoside improves non‐alcoholic fatty liver disease by promoting PINK1‐mediated mitophagy in mice

Shi

Zhu

et al. 2020

British J Pharmacology

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Background and Purpose: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. Experimental Approach: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. Key Results: C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. Conclusion and Implications: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment. 1 | INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide and is defined as the accumulation of fat in the liver in individuals who do not consume excessive alcohol. The global prevalence of non-alcoholic fatty liver disease is 25.24% and nonalcoholic fatty liver disease may progress to non-alcoholic steatohepatitis and cirrhosis or progress directly to hepatocellular carcinoma (Younossi et al., 2016). However, no pharmacological treatment approved by the US Food and Drug Administration is currently available.

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Section: Methodsmentioning

confidence: 99%

Cyanidin‐3‐O‐glucoside improves non‐alcoholic fatty liver disease by promoting PINK1‐mediated mitophagy in mice

Shi

Zhu

et al. 2020

British J Pharmacology

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“…In this context, plant polyphenols are likely good candidates since several of these well‐known antioxidant compounds are now widely regarded as pharmacological agents that regulate target proteins and associated signalling pathways including in pancreatic beta cells (Dall'Asta et al, ; Goszcz, Duthie, Stewart, Leslie, & Megson, ; Oak et al, ; Saponara, Carosati, Mugnai, Sgaragli, & Fusi, ). The possibility of developing polyphenol‐based therapeutics is further supported by studies reporting that a number of polyphenols elicit therapeutic‐like effects at pharmacological micromolar concentrations in cells, tissues, and various animal models (Bai et al, ; Gu et al, ; Wright, ; Zhao et al, ). However and in contrast to the naturally occurring plant polyphenols, the bioactivity of their metabolite derivatives has more recently emerged and hence is still poorly characterized (Del Rio et al, ; Espín, Larrosa, García‐Conesa, & Tomás‐Barberán, ; Goszcz et al, ).…”

Section: Introductionmentioning

confidence: 99%

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Bayle

Neasta

Dall’Asta

et al. 2019

British J Pharmacology

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Background and Purpose The pharmacology of polyphenol metabolites on beta‐cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin‐secreting function of beta‐cells and to explore the underlying mechanisms. Experimental Approach INS‐1 beta‐cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole‐cell patch‐clamp recordings were used for mechanistic studies. Key Results Among a set of polyphenol metabolites, we found that exposure of INS‐1 beta‐cells to urolithins A and C enhanced glucose‐stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose‐dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non‐stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav1.2 L‐type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization‐induced increase in intracellular Ca2+ in INS‐1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose‐dependently enhanced the L‐type Ca2+ current for levels of depolarization above threshold and shifted its voltage‐dependent activation towards more negative potentials in INS‐1 cells. Conclusion and Implications Urolithin C is a glucose‐dependent activator of insulin secretion acting by facilitating L‐type Ca2+ channel opening and Ca2+ influx into pancreatic beta‐cells. Our work paves the way for the design of polyphenol metabolite‐inspired compounds aimed at ameliorating beta‐cell function.

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“…Notably, MH, one of the most widely distributed flavonoids in plants, possesses strong free radical scavenging ability and potent hepatoprotective effects (Caselli et al, 2016; Lee et al, 2016; Naowaboot et al, 2016). Several studies in animal models have demonstrated that the administration of morin significantly prevented liver injury, inflammation, and fibrosis (Rizvi et al, 2015; Gu et al, 2017; Perumal et al, 2017; Tian et al, 2017; Li et al, 2018). For example, MH attenuated acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism (Rizvi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…MH has been reported to possess antioxidant, neuroprotective, anti-inflammatory, antihypertensive, and anticancer properties (Dong et al, 2015; Caselli et al, 2016; Lee et al, 2016; Naowaboot et al, 2016). In particular, MH has also shown to inhibit liver injury, inflammation, and fibrosis in several different animal models by its antioxidant and anti-inflammatory effects (Rizvi et al, 2015; Gu et al, 2017; Perumal et al, 2017; Tian et al, 2017). However, the exact molecular mechanism underlying the hepatoprotective effect of MH is still partially understood.…”

Section: Introductionmentioning

confidence: 99%

Morin Hydrate Inhibits TREM-1/TLR4-Mediated Inflammatory Response in Macrophages and Protects Against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

Yao

Huang

et al. 2019

Front. Pharmacol.

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This study aims to investigate the protective effects of morin hydrate (MH) against acute liver injury induced by carbon tetrachloride (CCl4) in mice and to elucidate the possible molecular mechanism of action. Mice were pretreated with MH (50 mg/kg body weight) or vehicle by oral gavage once daily for 5 days, followed by intraperitoneal injection of a single dose of CCl4 (1 ml/kg in olive oil). Mice were sacrificed 24 h later; the blood and liver samples were harvested for analysis. We also used the model of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in vitro and examined the effects of MH and its mechanism of action on the inflammatory response. Our results revealed that MH remarkably attenuated liver histopathological alterations, serum transaminases, hepatocytes death, and inflammatory response induced by CCl4. Importantly, MH reduced expression of the triggering receptor expressed on myeloid cells-1 (TREM-1) and toll-like receptor 4 (TLR4) both in vivo and in vitro experiments. This inhibitory effect MH on expression of the TREM-1 and TLR4 in cell culture was further heightened after TREM-1 knockdown with small interfering RNA (siRNA). Moreover, MH dramatically suppressed the inhibitor of kappa B α (IκBα) degradation and subsequent nuclear factor-kappa B (NF-κB) p65 translocation into the nucleus and NF-κB-mediated cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6. Additionally, MH also ameliorated CCl4-induced oxidative stress by enhancing the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in the injured livers. Taken together, MH has hepatoprotective activity, and this effect may be elicited by attenuating macrophage-mediated inflammatory responses via inhibition TREM-1/TLR4/NF-κB signaling and by regulating hepatic oxidative stress via enhancement Nrf2/HO-1 antioxidant pathway.

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Morin, a novel liver X receptor α/β dual antagonist, has potent therapeutic efficacy for nonalcoholic fatty liver diseases

Cited by 34 publications

References 64 publications

Cyanidin‐3‐O‐glucoside improves non‐alcoholic fatty liver disease by promoting PINK1‐mediated mitophagy in mice

Cyanidin‐3‐O‐glucoside improves non‐alcoholic fatty liver disease by promoting PINK1‐mediated mitophagy in mice

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Morin Hydrate Inhibits TREM-1/TLR4-Mediated Inflammatory Response in Macrophages and Protects Against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

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