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miRNAs in non-alcoholic fatty liver disease

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《医学前沿（英文）》 2016年 第10卷 第4期   页码 389-396 doi: 10.1007/s11684-016-0468-5

摘要：

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver cirrhosis and hepatocellular carcinoma and is a considerable threat to public health. miRNAs are important post-transcriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. Recently, a number of studies have described the association between miRNAs and NAFLD progression and have shown that circulating miRNAs reflect histological changes in the liver. Therefore, circulating miRNAs have potential use for the evaluation of NAFLD severity. In this review, we discuss the involvement of miRNAs in NAFLD pathogenesis and the key role of miRNAs in the screening, diagnosis, and staging of NAFLD.

关键词： nonalcoholic fatty liver disease     nonalcoholic steatohepatitis     hepatocellular carcinoma     miRNA    

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Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge

《医学前沿（英文）》 2022年 第16卷 第5期   页码 667-685 doi: 10.1007/s11684-022-0960-z

摘要： Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer. Akkermansia muciniphila (A. muciniphila) is a next-generation probiotic that has been reported to improve metabolic disorders. Emerging evidence indicates the therapeutic potential of A. muciniphila for NAFLD, especially in the inflammatory stage, nonalcoholic steatohepatitis. Here, the current knowledge on the role of A. muciniphila in the progression of NAFLD was summarized. A. muciniphila abundancy is decreased in animals and humans with NAFLD. The recovery of A. muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD. The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed. The modulation mechanisms by which A. muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells (such as macrophages). This review provides insights into the roles of A. muciniphila in NAFLD, thereby providing a blueprint to facilitate clinical therapeutic applications.

关键词： Akkermansia muciniphila     NAFLD     NASH     steatosis     inflammation    

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Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in A Macrophage-Specific and Liver-Specific Manner

Hengdong Qu,Di Zhang,Junli Liu,Jieping Deng,Ruoyan Xie,Keke Zhang,Hongmei Li,Ping Tao,Genshu Wang,Jian Sun,Oscar Junhong Luo,Chen Qu,Wencai Ye,Jian Hong,

《工程（英文）》 doi: 10.1016/j.eng.2024.05.005

摘要： Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, representing a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

关键词： Pyruvate kinase M2     Macrophages     nonparenchymal cells     heteroduplex oligonucleotide     Nonalcoholic steatohepatitis     Liver fibrosis    

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Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to

Yang Song,Wei Zhong,Harry Cheuk-Hay Lau,Yating Zhang,Huayu Guan,Mingxu Xie,Suki Ha,Diwen Shou,Yongjian Zhou,Hongzhi Xu,Jun Yu,Xiang Zhang,

《工程（英文）》 doi: 10.1016/j.eng.2024.04.018

摘要： Carboxyl ester lipase (CEL), a pivotal enzyme involved in lipid metabolism, is recurrently mutated in obese mice. Here, we aimed to elucidate the functional significance, molecular mechanism, and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific Cel knockout (CelΔHEP) and wildtype (WT) littermates were fed with choline-deficient high-fat diet (CD-HFD) for 16 weeks, or methionine- and choline-deficient diet (MCD) for 3 weeks to induce MASH. Liquid chromatography-mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL. CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral, serotype 8 (AAV8) to induce specific overexpression of CEL in the liver. We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice. CelΔHEP mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis, inflammation, lipid peroxidation, and liver injury compared to WT littermates, accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. Consistently, Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation, whereas CEL overexpression exerted the opposite effect. Mechanistically, CEL directly bound to fatty acid synthase (FASN), resulting in reduced FASN SUMOylation, which in turn promoted FASN degradation through the proteasome pathway. Furthermore, inhibition of FASN using small interfering RNA (siRNA) or TVB-3664 ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro. Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD. CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis. CEL overexpression confers a therapeutic benefit in steatohepatitis.

关键词： Metabolic dysfunction-associated steatohepatitis     Carboxyl ester lipase     Fatty acid synthase     De novo lipogenesis     Treatment    

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Pathological study of 130 cases of nonalcoholic fatty liver disease based on NASH-CRN system

ZHOU Guangde, ZHAO Jingmin, DING Xiaohui, PAN Deng, SUN Yanling, YANG Jianfa, ZHAO Yulai

《医学前沿（英文）》 2007年 第1卷 第4期   页码 413-417 doi: 10.1007/s11684-007-0081-8

摘要： To summarize the pathological features of nonalcoholic liver disease (NAFLD) in China based on a histological scoring system for NAFLD designed by the Pathology Committee of NASH Clinical Research Network (NASH-CRN), the specimens of liver needle biopsies from 130 patients with NAFLD were histopathologically analyzed by haematoxylin eosin, reticular fiber and Masson trichrome stain. Immunohistochemistry staining was used to exclude non-NAFLD cases combined with clinical data. Hepatic steatosis, lobular inflammation, hepatocytic ballooning and fibrosis were presented widespread in NAFLD liver tissues. Furthermore, macrovesicular steatosis predominantly located in acinar zone 3 was the main histologic feature of NAFLD and lobular inflammation was usually presented mildly. Hepatocyte ballooning was observed in 94.6% of all 130 cases. Mild perisinusoidal fibrosis and periportal fibrosis were often observed in stage 1 cases. According to the statistic analysis, hepatic steatosis was positively correlated with lobular inflammation, hepatocytic ballooning and fibrosis ( = 0.587, 0.488, 0.374, respectively, all value<0.01). The number of microgranulomas, lipogranulomas and apoptotic bodies increased following severity of steatosis, lobular inflammation and fibrosis. Meanwhile, the number of megamitochondria and glycogen nuclei was paralleveled to the degree of hepatocytic ballooning ( value all<0.01). We suggest that the role of portal inflammation should be emphasized besides hepatic steatosis, lobular inflammation, hepatocyte ballooning and fibrosis in diagnosis and evaluation of NAFLD. It needs to be further verified whether microgranulomas, lipogranulomas and apoptosis bodies could be used as histopathological markers of development of AFLD. The number of megamitochondria is more frequently be found in NAFLD, while in alcoholic liver diseases was Mallory bodies.
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Molecular mechanisms of fatty liver in obesity

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《医学前沿（英文）》 2015年 第9卷 第3期   页码 275-287 doi: 10.1007/s11684-015-0410-2

摘要：

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

关键词： nonalcoholic fatty liver disease     insulin resistance     obesity    

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Low-carbohydrate diets lead to greater weight loss and better glucose homeostasis than exercise: a randomized clinical trial

《医学前沿（英文）》 2021年 第15卷 第3期   页码 460-471 doi: 10.1007/s11684-021-0861-6

摘要： Lifestyle interventions, including dietary adjustments and exercise, are important for obesity management. This study enrolled adults with overweight or obesity to explore whether either low-carbohydrate diet (LCD) or exercise is more effective in metabolism improvement. Forty-five eligible subjects were randomly divided into an LCD group (n=22) and an exercise group (EX, n=23). The subjects either adopted LCD (carbohydrate intake<50 g/day) or performed moderate-to-vigorous exercise (≥30 min/day) for 3 weeks. After the interventions, LCD led to a larger weight loss than EX (−3.56±0.37 kg vs. −1.24±0.39 kg, P<0.001), as well as a larger reduction in fat mass (−2.10±0.18 kg vs. −1.25±0.24 kg, P=0.007) and waist circumference (−5.25±0.52 cm vs. −3.45±0.38 cm, P=0.008). Both interventions reduced visceral and subcutaneous fat and improved liver steatosis and insulin resistance. Triglycerides decreased in both two groups, whereas low-density lipoprotein cholesterol increased in the LCD group but decreased in the EX group. Various glycemic parameters, including serum glycated albumin, mean sensor glucose, coefficient of variability (CV), and largest amplitude of glycemic excursions, substantially declined in the LCD group. Only CV slightly decreased after exercise. This pilot study suggested that the effects of LCD and exercise are similar in alleviating liver steatosis and insulin resistance. Compared with exercise, LCD might be more efficient for weight loss and glucose homeostasis in people with obesity.

关键词： low-carbohydrate diet     obesity     nonalcoholic fatty liver disease     continuous glucose monitoring     mean sensor glucose    

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片仔癀通过调节小鼠的肠道菌群和代谢物抑制非酒精性脂肪性肝炎 Article

曾宪一, 张翔, 苏浩, 苟红艳, 刘焯晞, 胡晓旭, 黄子恒, 李艳, 于君

《工程（英文）》 2024年 第35卷 第4期   页码 257-269 doi: 10.1016/j.eng.2022.10.010

摘要：

非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病(NAFLD)的进展阶段，目前尚无有效的治疗方法。传统中药片仔癀具有抗炎作用。本研究评估了片仔癀在NASH防治中的作用及潜在机制。研究结果显示，片仔癀能有效预防由多种饮食[包括高脂高胆固醇饮食（HFHC）、胆碱缺乏的高脂饮食（CD-HFD）以及蛋氨酸胆碱缺乏饮食（MCD）]引起的NASH进展，同时显著抑制肝损伤、肝脏甘油三酯聚集和脂质过氧化。此外，片仔癀可治疗MCD饮食诱导的NASH，显著改善小鼠的脂肪变和肝损伤。通过对小鼠粪便样本进行宏基因组测序分析，我们发现片仔癀可修复肠道菌群失衡，显著增加包括乳酸杆菌、植物乳杆菌、乳酸链球菌以及枯草杆菌等在内的有益菌的丰度。而乳酸杆菌能有效抑制由MCD饮食诱导的NASH进展。此外, 片仔癀可以恢复脂肪肝病变小鼠的肠道屏障功能，表现为肠道通透性降低，血清内毒素水平下降，以及上皮紧密连接蛋白E-cadherin表达增加。利用液相色谱-质谱联用技术进行代谢分析，发现片仔癀处理过的小鼠门静脉中胆汁酸代谢发生显著变化。进一步分析发现，完整的肠道菌群在片仔癀抗NASH作用中不可或缺。总之，片仔癀通过调节肠道菌群和代谢物发挥抑制NASH的作用，有望成为NASH防治的潜在药物。

关键词： 片仔癀     非酒精性脂肪性肝病     肠黏膜屏障     肠道菌群    

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NKT cells in liver diseases

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《医学前沿（英文）》 2018年 第12卷 第3期   页码 249-261 doi: 10.1007/s11684-018-0622-3

摘要：

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells.

关键词： natural killer T cells     hepatitis B virus and hepatitis C virus infection     autoimmune liver diseases     alcoholic liver disease     nonalcoholic fatty liver disease     hepatocellular carcinoma    

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肠道菌群与肿瘤发生及肝病

吕桂帅, 程宁涛, 王红阳

《工程（英文）》 2017年 第3卷 第1期   页码 110-114 doi: 10.1016/J.ENG.2017.01.017

摘要：

一个多世纪以前，科学家们就首次发现了肿瘤区域中细菌的存在。但是，微生物在肿瘤发生中的作用近年来才被认识到。近几十年来，与肠道菌群失调相关的疾病代表了全世界最严重的一些公共卫生问题。大量的流行病学研究表明，肠道菌群与某些常见肿瘤密切相关。然而，肠道菌群与肿瘤相关联的具体分子机制仍不明确。研究表明，肠道菌群的改变有助于确定肝癌、酒精相关肝病、非酒精性脂肪肝和肝硬化的发生和发展。鉴于益生菌是一种可通过调节免疫系统促进人类健康的药物，其可能会为肝细胞癌(HCC) 和非酒精性脂肪肝的治疗提供新方向。本文总结了肠道菌群在肿瘤及肝病中的研究进展，综述了肠道菌群与肿瘤和肝病之间的关系。此外，考虑到细菌内稳态的重要性，我们也对益生菌进行了概述，旨在为相关疾病的治疗提供指导。

关键词： 肠道菌群     稳态失调     肿瘤发生     肝细胞癌     非酒精性脂肪性肝病    

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标题 作者 时间 类型 操作

miRNAs in non-alcoholic fatty liver disease

null

期刊论文

Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge

期刊论文

Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in A Macrophage-Specific and Liver-Specific Manner

Hengdong Qu,Di Zhang,Junli Liu,Jieping Deng,Ruoyan Xie,Keke Zhang,Hongmei Li,Ping Tao,Genshu Wang,Jian Sun,Oscar Junhong Luo,Chen Qu,Wencai Ye,Jian Hong,

期刊论文

Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to

Yang Song,Wei Zhong,Harry Cheuk-Hay Lau,Yating Zhang,Huayu Guan,Mingxu Xie,Suki Ha,Diwen Shou,Yongjian Zhou,Hongzhi Xu,Jun Yu,Xiang Zhang,

期刊论文

Pathological study of 130 cases of nonalcoholic fatty liver disease based on NASH-CRN system

ZHOU Guangde, ZHAO Jingmin, DING Xiaohui, PAN Deng, SUN Yanling, YANG Jianfa, ZHAO Yulai

期刊论文

Molecular mechanisms of fatty liver in obesity

null

期刊论文

Low-carbohydrate diets lead to greater weight loss and better glucose homeostasis than exercise: a randomized clinical trial

期刊论文

片仔癀通过调节小鼠的肠道菌群和代谢物抑制非酒精性脂肪性肝炎

曾宪一, 张翔, 苏浩, 苟红艳, 刘焯晞, 胡晓旭, 黄子恒, 李艳, 于君

期刊论文

NKT cells in liver diseases

null

期刊论文

肠道菌群与肿瘤发生及肝病

吕桂帅, 程宁涛, 王红阳

期刊论文