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Singh A, Chaudhary R. Potentials of peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ: An in-depth and comprehensive review of their molecular mechanisms, cellular Signalling, immune responses and therapeutic implications in multiple diseases. Int Immunopharmacol 2025; 155:114616. [PMID: 40222274 DOI: 10.1016/j.intimp.2025.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.
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Affiliation(s)
- Alpana Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
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2
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Iwaki M, Kobayashi T, Nogami A, Ogawa Y, Imajo K, Sakai E, Nakada Y, Koyama S, Kurihashi T, Oza N, Kohira T, Okada M, Yamaguchi Y, Iwane S, Kageyama F, Sasada Y, Matsushita M, Tadauchi A, Murohisa G, Nagasawa M, Sato S, Maeda K, Furuta K, Shigefuku R, Seko Y, Tobita H, Kawata K, Kawanaka M, Sugihara T, Tamaki N, Iwasa M, Kawaguchi T, Itoh Y, Kawaguchi A, Takahashi H, Nakajima A, Yoneda M. Pemafibrate for treating MASLD complicated by hypertriglyceridaemia: a multicentre, open-label, randomised controlled trial study protocol. BMJ Open 2024; 14:e088862. [PMID: 39581726 PMCID: PMC11590823 DOI: 10.1136/bmjopen-2024-088862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 10/25/2024] [Indexed: 11/26/2024] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH. METHODS AND ANALYSIS This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20-80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities. ETHICS AND DISSEMINATION Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. Participants wishing to understand the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280). PROTOCOL VERSION V.1.9, 23 November 2023.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, National Hospital Organisation Yokohama Medical Center, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology, Shin Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan
| | - Eiji Sakai
- Department of Gastroenterology, Yokohama Sakae Kyosai Hospital, Yokohama, Japan
| | - Yoshinobu Nakada
- Department of Internal Medicine, Shonan Hospital, Yokosuka, Kanagawa, Japan
| | - Satoshi Koyama
- Department of Internal Medicine, NamikiKoiso-Medical Clinic, Yokohama, Japan
| | - Takeo Kurihashi
- Department of Internal Medicine, Kanagawa Dental University Yokohama Clinic, Yokohama, Japan
| | - Noriko Oza
- Department of Hepato-Biliary-Pancreatology, Saga Prefecture Medical Center Koseikan, Saga, Saga, Japan
| | | | - Michiaki Okada
- Department of Internal Medicine, Karatsu Red Cross Hospital, Karatsu, Japan
| | - Yuki Yamaguchi
- Department of Internal Medicine, Masuda Red Cross Hospital, Masuda, Japan
| | - Shinji Iwane
- Department of Internal Medicine, Fujioka Hospital, Saga, Japan
| | - Fujito Kageyama
- Department of Gastroenterology and Hepatology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan
| | - Yuzo Sasada
- Division of Hepatology, Iwata City Hospital, Iwata, Japan
| | | | - Akimitsu Tadauchi
- Department of Gastroenterology, Seirei Mikatahara Byoin, Hamamatsu, Shizuoka, Japan
| | - Gou Murohisa
- Department of Gastroenterology, Seirei Hamamatsu Byoin, Hamamatsu, Shizuoka, Japan
| | - Masamichi Nagasawa
- Department of Gastroenterology, Seirei Hamamatsu Byoin, Hamamatsu, Shizuoka, Japan
| | - Shuichi Sato
- Department of Internal Medicine, Izumo City General Medical Center, Izumo, Japan
| | - Kazuhisa Maeda
- Department of Internal Medicine, Kitasenri Maeda Clinic, Suita, Japan
| | - Koichiro Furuta
- Department of Gastroenterology, National Hospital Organization Hamada Medical Center, Hamada, Japan
| | - Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine Faculty of Medicine, Tsu, Mie, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, Shimane, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical Center, Kawasaki Medical School, Kurashiki, Japan
| | - Takaaki Sugihara
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine Graduate School of Medicine, Yonago, Tottori, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine Faculty of Medicine, Tsu, Mie, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Liver Center, Saga University Hospital, Saga, Saga, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
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Fan S, Gao Y, Zhao P, Xie G, Zhou Y, Yang X, Li X, Zhang S, Gonzalez FJ, Qu A, Huang M, Bi H. Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR α-dependent and partially related to the YAP pathway. Acta Pharm Sin B 2024; 14:2992-3008. [PMID: 39027236 PMCID: PMC11252459 DOI: 10.1016/j.apsb.2024.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/26/2024] [Accepted: 03/03/2024] [Indexed: 07/20/2024] Open
Abstract
Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP-TEAD complex. Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
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Affiliation(s)
- Shicheng Fan
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Pengfei Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yanying Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xiao Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
| | - Xuan Li
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shuaishuai Zhang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Huichang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
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Fang Z, Shen G, Wang Y, Hong F, Tang X, Zeng Y, Zhang T, Liu H, Li Y, Wang J, Zhang J, Gao A, Qi W, Yang X, Zhou T, Gao G. Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease. Signal Transduct Target Ther 2024; 9:66. [PMID: 38472195 PMCID: PMC10933339 DOI: 10.1038/s41392-024-01781-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 02/14/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.
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Affiliation(s)
- Zhenzhen Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Gang Shen
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yina Wang
- Department of VIP Medical Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Fuyan Hong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiumei Tang
- Physical Examination Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yongcheng Zeng
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ting Zhang
- Department of Clinical Laboratory, Guangzhou First People's Hospital, Guangzhou, 510080, China
| | - Huanyi Liu
- Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yanmei Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jinhong Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jing Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Anton Gao
- Department of Health Sciences, College of Health Solutions, Arizona State University, Tempe, USA
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xia Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Ti Zhou
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Diabetology, Guangzhou, 510080, China.
| | - Guoquan Gao
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Changizi Z, Kajbaf F, Moslehi A. An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases. J Clin Transl Hepatol 2023; 11:1542-1552. [PMID: 38161499 PMCID: PMC10752810 DOI: 10.14218/jcth.2023.00334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/17/2023] [Accepted: 10/09/2023] [Indexed: 01/03/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.
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Affiliation(s)
- Zahra Changizi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Forough Kajbaf
- Veterinary Department, Faculty of Agriculture, Islamic Azad University, Shoushtar Branch, Shoushtar, Iran
| | - Azam Moslehi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
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Rodimova S, Bobrov N, Mozherov A, Elagin V, Karabut M, Ermakova P, Shchechkin I, Kozlov D, Krylov D, Gavrina A, Kashina A, Zagainov V, Zagaynova E, Kuznetsova D. The Effect of Diabetes Mellitus Type 1 on the Energy Metabolism of Hepatocytes: Multiphoton Microscopy and Fluorescence Lifetime Imaging. Int J Mol Sci 2023; 24:17016. [PMID: 38069338 PMCID: PMC10706954 DOI: 10.3390/ijms242317016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
A decrease in the regenerative potential of the liver during the development of non-alcoholic fatty liver disease (NAFLD), which is observed in the vast majority of patients with diabetes mellitus type 1, significantly increases the risk of postoperative liver failure. In this regard, it is necessary to develop new approaches for the rapid intraoperative assessment of the condition of liver tissue in the presence of concomitant liver pathology. A modern label-free approach based on multiphoton microscopy, second harmonic generation (SHG), and fluorescence lifetime imaging microscopy (FLIM) allow for the evaluation of the structure of liver tissue as well as the assessment of the metabolic state of hepatocytes, even at the cellular level. We obtained optical criteria and identified specific changes in the metabolic state of hepatocytes for a reduced liver regenerative potential in the presence of induced diabetes mellitus type 1. The obtained criteria will expand the possibilities for the express assessment of the structural and functional state of liver tissue in clinical practice.
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Affiliation(s)
- Svetlana Rodimova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
| | - Nikolai Bobrov
- The Volga District Medical Centre of Federal Medical and Biological Agency, 14 Ilinskaya St., 603000 Nizhny Novgorod, Russia
| | - Artem Mozherov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Vadim Elagin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
| | - Maria Karabut
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
| | - Polina Ermakova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
| | - Ilya Shchechkin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Kozlov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Krylov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Alena Gavrina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Aleksandra Kashina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
| | - Vladimir Zagainov
- The Volga District Medical Centre of Federal Medical and Biological Agency, 14 Ilinskaya St., 603000 Nizhny Novgorod, Russia
- Nizhny Novgorod Regional Clinical Oncologic Dispensary, 11/1 Delovaya St., 603126 Nizhny Novgorod, Russia
| | - Elena Zagaynova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya St., 119435 Moscow, Russia
| | - Daria Kuznetsova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia; (S.R.); (V.E.); (D.K.); (D.K.)
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
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Bołdys A, Bułdak Ł, Maligłówka M, Surma S, Okopień B. Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1789. [PMID: 37893507 PMCID: PMC10608225 DOI: 10.3390/medicina59101789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023]
Abstract
Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.
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Affiliation(s)
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
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Wang L, Yan Y, Wu L, Peng J. Natural products in non-alcoholic fatty liver disease (NAFLD): Novel lead discovery for drug development. Pharmacol Res 2023; 196:106925. [PMID: 37714392 DOI: 10.1016/j.phrs.2023.106925] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023]
Abstract
With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence, mortality, and associated burden of NAFLD-related advanced liver disease is expected. Currently, the initial diagnosis of NAFLD is still based on ultrasound and there is no approved treatment method. Lipid-lowering drugs, vitamin supplementation, and lifestyle improvement treatments are commonly used in clinical practice. However, most lipid-lowering drugs can produce poor patient compliance and specific adverse effects. Therefore, the exploration of bio-diagnostic markers and active lead compounds for the development of innovative drugs is urgently needed. More and more studies have reported the anti-NAFLD effects and mechanisms of natural products (NPs), which have become an important source for new drug development to treat NAFLD due to their high activity and low side effects. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies, demonstrating the potential of NPs against NAFLD. Studies have found that the regulation of lipid metabolism, insulin resistance, oxidative stress, and inflammation-related pathways may play important roles in the process. With the continuous updating of technical means and scientific theories, in-depth research on the targets and mechanisms of NPs against NAFLD can provide new possibilities to find bio-diagnostic markers and innovative drugs. As we know, FXR agonists, PPARα agonists, and dual CCR2/5 inhibitors are gradually coming on stage for the treatment of NAFLD. Whether NPs can exert anti-NAFLD effects by regulating these targets or some unknown targets remains to be further studied. Therefore, the study reviewed the potential anti-NAFLD NPs and their targets. Some works on the discovery of new targets and the docking of active lead compounds were also discussed. It is hoped that this review can provide some reference values for the development of non-invasive diagnostic markers and new drugs against NAFLD in the clinic.
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Affiliation(s)
- Lu Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Yonghuan Yan
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Linfang Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Jinyong Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
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Yan BF, Pan LF, Quan YF, Sha Q, Zhang JZ, Zhang YF, Zhou LB, Qian XL, Gu XM, Li FT, Wang T, Liu J, Zheng X. Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway. World J Gastroenterol 2023; 29:4744-4762. [PMID: 37664157 PMCID: PMC10473922 DOI: 10.3748/wjg.v29.i31.4744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/23/2023] [Accepted: 07/31/2023] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological entity characterized by intrahepatic ectopic steatosis. As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle, the incidence of NAFLD has surpassed that of viral hepatitis, making it the most common cause of chronic liver disease globally. Huangqin decoction (HQD), a Chinese medicinal formulation that has been used clinically for thousands of years, has beneficial outcomes in patients with liver diseases, including NAFLD. However, the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood. AIM To evaluate the ameliorative effects of HQD in NAFLD, with a focus on lipid metabolism and insulin resistance, and to elucidate the underlying mechanism of action. METHODS High-fat diet-induced NAFLD rats and palmitic acid (PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action. Phytochemicals in HQD were analyzed by high-performance liquid chromatography (HPLC) to identify the key components. RESULTS Ten primary chemical components of HQD were identified by HPLC analysis. In vivo, HQD effectively prevented rats from gaining body and liver weight, improved the liver index, ameliorated hepatic histological aberrations, decreased transaminase and lipid profile disorders, and reduced the levels of pro-inflammatory factors and insulin resistance. In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation, inflammation, and insulin resistance in HepG2 cells. In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathway-modulated lipogenesis and inflammation, contributing to its beneficial actions, which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD. CONCLUSION In summary, our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.
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Affiliation(s)
- Bao-Fei Yan
- College of Pharmacy, Jiangsu Health Vocational College, Nanjing 211800, Jiangsu Province, China
| | - Lan-Fen Pan
- Department of Pathology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu Province, China
| | - Yi-Fang Quan
- Department of Education and Science, The First People's Hospital of Taicang, Kunshan 215400, Jiangsu Province, China
| | - Qian Sha
- Department of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Jing-Zheng Zhang
- College of Pharmacy, Jiangsu Health Vocational College, Nanjing 211800, Jiangsu Province, China
| | - Yi-Feng Zhang
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Li-Bing Zhou
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu Province, China
| | - Xi-Long Qian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Xiao-Mei Gu
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu Province, China
| | - Feng-Tao Li
- College of Pharmacy, Jiangsu Health Vocational College, Nanjing 211800, Jiangsu Province, China
| | - Ting Wang
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu Province, China
| | - Jia Liu
- College of Pharmacy, Jiangsu Health Vocational College, Nanjing 211800, Jiangsu Province, China
| | - Xian Zheng
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu Province, China
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Gagnon E, Manikpurage HD, Mitchell PL, Girard A, Gobeil É, Bourgault J, Bégin F, Marette A, Thériault S, Arsenault BJ. Large-scale metabolomic profiling and incident non-alcoholic fatty liver disease. iScience 2023; 26:107127. [PMID: 37456853 PMCID: PMC10339047 DOI: 10.1016/j.isci.2023.107127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/11/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032 UK Biobank participants. We identified several metabolic factors associated with NAFLD risk in observational and MR analyses including triglyceride-rich and high-density lipoprotein particles composition, as well as the ratio of polyunsaturated fatty acids to total fatty acids. This study, is one of the largest to investigate incident NAFLD, provides concordant observational and genetic evidence that therapies aimed at reducing circulating triglycerides and increasing large HDL particles, as well as interventions aimed at increasing polyunsaturated fatty acid content may warrant further investigation into NAFLD prevention and treatment.
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Affiliation(s)
- Eloi Gagnon
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Hasanga D. Manikpurage
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Patricia L. Mitchell
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Arnaud Girard
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Émilie Gobeil
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Jérôme Bourgault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Frédéric Bégin
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - André Marette
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Québec (QC), Canada
| | - Sébastien Thériault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec (QC), Canada
| | - Benoit J. Arsenault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Québec (QC), Canada
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Wang X, Luo J, Lu Z, Fang S, Sun M, Luo W, Shen J, Liu A, Ye H. Therapeutic effect of fenofibrate for non-alcoholic steatohepatitis in mouse models is dependent on regime design. Front Pharmacol 2023; 14:1190458. [PMID: 37251331 PMCID: PMC10213340 DOI: 10.3389/fphar.2023.1190458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/03/2023] [Indexed: 05/31/2023] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases. In most cases, NAFLD progresses from benign steatosis to steatohepatitis (NASH), and then to cirrhosis. No treatment is currently approved for NAFLD/NASH in the clinic. Fenofibrate (FENO) has been clinically used to treat dyslipidemia for more than a half century, but its effects on NASH are not established. FENO's half-life is quite different between rodent and human. The aim of this study was to investigate the potential of pharmacokinetic-based FENO regime for NASH treatment and the underlying mechanisms. Methods: Two typical mouse NASH models, methionine-choline deficient (MCD) diet-fed mice and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, were used. MCD model was designed as therapeutic evaluation in experiment 1 and CDAHFD model was designed as preventive in experiment 2. Three doses of FENO (5, 25, 125 mg/kg), two times a day (BID), were administered to the above models. Serum markers of liver injury, cholestasis, and the histology of liver tissues were investigated. Normal mice were used as a model in experiment 3 for toxicity evaluation, Quantitative-PCR and Western Blot assays were used to investigate the inflammatory responses, bile acid synthesis as well as lipid catabolism. Results: Mice on the MCD and CDAHFD diets developed steatohepatitis as expected. Treatment with FENO (25 mg/kg·BID) significantly decreased hepatic steatosis, inflammation and fibrosis in both therapeutic and preventive models. In the MCD model, the therapeutic action of FENO (25 mg/kg·BID) and 125 mg/kg·BID on histopathology and the expression of inflammatory cytokines were comparable. In reducing macrophage infiltration and bile acid load, FENO (25 mg/kg·BID) was superior to 125 mg/kg·BID. In all the aspects mentioned above, FENO (25 mg/kg·BID) was the best among the 3 doses in the CDAHFD model. In a third experiment, the effects of FENO (25 mg/kg·BID) and 125 mg/kg·BID on lipid catabolism were comparable, but 125 mg/kg·BID increased the expression of inflammatory factors and bile acid load. In both models, FENO (5 mg/kg·BID) showed little effect in hepatic steatosis and inflammation, neither the adverse effects. FENO (125 mg/kg·BID) aggravated liver inflammation, increased bile acid synthesis, and promoted the potential of liver proliferation. In toxicity risk assay, FENO (25 mg/kg·BID) treatment showed low potential to trigger bile acid synthesis, inflammation and hepatocyte proliferation. Conclusion: A new regime, FENO (25 mg/kg·BID) is potentially a therapeutic strategy for the NASH treatment. Translational medicine is warranted to prove its effectiveness in the clinic.
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Affiliation(s)
- Xinxue Wang
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jia Luo
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Zhuoheng Lu
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Shenzhe Fang
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Mengxia Sun
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Wenjing Luo
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jianwei Shen
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Aiming Liu
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Hua Ye
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
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Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials. Int J Mol Sci 2022; 24:ijms24010158. [PMID: 36613602 PMCID: PMC9820446 DOI: 10.3390/ijms24010158] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/24/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups-hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.
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Warzecha KW, Pudełek M, Catapano J, Madeja Z, Czyż J. Long-Term Fenofibrate Treatment Stimulates the Phenotypic Microevolution of Prostate Cancer Cells In Vitro. Pharmaceuticals (Basel) 2022; 15:1320. [PMID: 36355492 PMCID: PMC9694160 DOI: 10.3390/ph15111320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 08/30/2023] Open
Abstract
Fenofibrate is a widely used anti-hyperlipidemic agonist of peroxisome proliferator-activated receptor alpha (PPARα). As a metabolic blocker, fenofibrate interferes with cancer promotion/progression via its misbalancing effects on cellular metabolism. However, the consequences of its long-term application for patients with diagnosed drug-resistant cancers are unknown. We addressed this point by tracing the phenotypic microevolution of naïve and drug-resistant prostate cancer PC3_DCX20 cells that underwent a long-term exposition to 10 μM and 50 μM fenofibrate. Their resistance to fenofibrate, metabolic profile and invasive phenotype were estimated in the control conditions and under fenofibrate-induced stress. Apparently, drug efflux systems are not effective against the cytostatic FF action. However, wtPC3 and PC3_DCX20 cells that survived the long-term 50 μM fenofibrate treatment gave rise to lineages that displayed an increased proliferation rate, lower motility in the control conditions and enhanced fenofibrate resistance. Attenuated fenofibrate bioavailability modified the pattern of PC3 microevolution, as illustrated by phenotypic differences between wtPC3/PC3_DCX20 lineages propagated in the presence of 50 μM and 10 μM fenofibrate. Collectively, our observations indicate that fenofibrate acts as a selective factor that affects prostate cancer microevolution. We also pinpoint potential consequences of long-term exposition of prostate cancer patients to metabolic blockers.
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Affiliation(s)
| | | | | | | | - Jarosław Czyż
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Cracow, Poland
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Mahmoudi A, Moallem SA, Johnston TP, Sahebkar A. Liver Protective Effect of Fenofibrate in NASH/NAFLD Animal Models. PPAR Res 2022; 2022:5805398. [PMID: 35754743 PMCID: PMC9232374 DOI: 10.1155/2022/5805398] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/19/2022] [Accepted: 06/02/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is initiated by excessive fat buildup in the liver, affecting around 35% of the world population. Various circumstances contribute to the initiation and progression of NAFLD, and it encompasses a wide range of disorders, from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. Although several treatments have been proposed, there is no definitive cure for NAFLD. In recent decades, several medications related to other metabolic disorders have been evaluated in preclinical studies and in clinical trials due to the correlation of NAFLD with other metabolic diseases. Fenofibrate is a fibrate drug approved for dyslipidemia that could be used for modulation of hepatic fat accumulation, targeting peroxisome proliferator-activator receptors, and de novo lipogenesis. This drug offers potential therapeutic efficacy for NAFLD due to its capacity to decrease the accumulation of hepatic lipids, as well as its antioxidant, anti-inflammatory, and antifibrotic properties. To better elucidate the pathophysiological processes underlying NAFLD, as well as to test therapeutic agents/interventions, experimental animal models have been extensively used. In this article, we first reviewed experimental animal models that have been used to evaluate the protective effects of fenofibrate on NAFLD/NASH. Next, we investigated the impact of fenofibrate on the hepatic microcirculation in NAFLD and then summarized the beneficial effects of fenofibrate, as compared to other drugs, for the treatment of NAFLD. Lastly, we discuss possible adverse side effects of fenofibrate on the liver.
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Affiliation(s)
- Ali Mahmoudi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Seyed Adel Moallem
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P. Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Mahmoudi A, Jamialahmadi T, Johnston TP, Sahebkar A. Impact of fenofibrate on NAFLD/NASH: A genetic perspective. Drug Discov Today 2022; 27:2363-2372. [PMID: 35569762 DOI: 10.1016/j.drudis.2022.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/13/2022] [Accepted: 05/09/2022] [Indexed: 11/26/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), caused by an accumulation of fat deposits in hepatocytes, prevalently affects at least one-third of the world's population. The progression of this disorder can potentially include a spectrum of consecutive stages, specifically: steatosis, steatohepatitis and cirrhosis. Fenofibrate exhibits potential therapeutic efficacy for NAFLD owing to several properties, which include antioxidant, apoptotic, anti-inflammatory and antifibrotic activity. In the present review, we discuss the direct or indirect impact of fenofibrate on genes involved at various stages in the progression of NAFLD. Moreover, we have reviewed studies that compare fenofibrate with other drugs in treating NAFLD, as well as recent clinical trials, in an attempt to identify reliable scientific and clinical evidence concerning the therapeutic effects and benefits of fenofibrate on NAFLD. Teaser.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9233650. [PMID: 35602098 PMCID: PMC9117022 DOI: 10.1155/2022/9233650] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines fat accumulation in the liver, and it is commonly associated with metabolic syndromes like diabetes and obesity. Progressive NAFLD leads to nonalcoholic steatohepatitis (NASH) and ultimately causes cirrhosis and hepatocellular carcinoma, and NASH is currently a frequent cause of liver transplantation. Oxidative stress is often contributed to the progression of NAFLD, and hence, antioxidants such as silymarin, silybin, or silibinin, pentoxifylline, resveratrol, and vitamins A, C, and E are used in clinical trials against NAFLD. Silymarin induces the peroxisome proliferator-activated receptor α (PPARα), a fatty acid sensor, which promotes the transcription of genes that are required for the enzymes involved in lipid oxidation in hepatocytes. Silybin inhibits sterol regulatory element-binding protein 1 and carbohydrate response element-binding protein to downregulate the expression of genes responsible for de novo lipogenesis by activating AMP-activated protein kinase phosphorylation. Pentoxifylline inhibits TNF-α expression and endoplasmic reticulum stress-mediated inflammatory nuclear factor kappa B (NF-κB) activation. Thus, it prevents NAFLD to NASH progression. Resveratrol inhibits methylation at Nrf-2 promoters and NF-κB activity via SIRT1 activation in NAFLD conditions. However, clinically, resveratrol has not shown promising beneficial effects. Vitamin C is beneficial in NAFLD patients. Vitamin E is not effectively regressing hepatic fibrosis. Hence, its combination with antifibrotic agents is used as an adjuvant to produce a synergistic antifibrotic effect. However, to date, none of these antioxidants have been used as a definite therapeutic agent in NAFLD patients. Further, these antioxidants should be studied in NAFLD patients with larger populations and multiple endpoints in the future.
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Tzanaki I, Agouridis AP, Kostapanos MS. Is there a role of lipid-lowering therapies in the management of fatty liver disease? World J Hepatol 2022; 14:119-139. [PMID: 35126843 PMCID: PMC8790403 DOI: 10.4254/wjh.v14.i1.119] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/30/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.
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Affiliation(s)
- Ismini Tzanaki
- School of Medicine, European University Cyprus, Nicosia, Cyprus, Nicosia 2404, Cyprus
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus
| | - Michael S Kostapanos
- General Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge CB20QQ, United Kingdom.
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18
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Mahmoudi A, Butler AE, Jamialahmadi T, Sahebkar A. Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3654660. [PMID: 34988225 PMCID: PMC8720586 DOI: 10.1155/2021/3654660] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 12/14/2021] [Indexed: 01/30/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. METHODS We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. RESULTS We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. CONCLUSION Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | | | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Willis SA, Bawden SJ, Malaikah S, Sargeant JA, Stensel DJ, Aithal GP, King JA. The role of hepatic lipid composition in obesity-related metabolic disease. Liver Int 2021; 41:2819-2835. [PMID: 34547171 DOI: 10.1111/liv.15059] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/15/2021] [Accepted: 09/17/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.
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Affiliation(s)
- Scott A Willis
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Stephen J Bawden
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK
| | - Sundus Malaikah
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jack A Sargeant
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester, UK
| | - David J Stensel
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - James A King
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
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20
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Abdallah MS, Eldeen AH, Tantawy SS, Mostafa TM. The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Eur J Pharmacol 2021; 906:174295. [PMID: 34214585 DOI: 10.1016/j.ejphar.2021.174295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/22/2021] [Accepted: 06/28/2021] [Indexed: 12/25/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with fat accumulation in the liver which can progress into non-alcoholic steatohepatitis (NASH). There is no specific treatment strategy for NASH. In this context, this study aimed at evaluating the efficacy and safety of montelukast in the treatment of patients with NASH. In this randomized double-blind placebo-controlled study, 52 overweight/obese patients with NASH were randomized into group 1 (n = 26) which received montelukast 10 mg tablets once daily and group 2 (n = 26) which received placebo tablets once daily for 12 weeks. The fibro-scan was used to assess liver stiffness as a primary outcome at baseline and 12 weeks post-treatment. Furthermore, patients were assessed for biochemical analysis of liver aminotransferases, metabolic parameters, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), liver fibrosis biomarkers including hyaluronic acid (HA) and transforming growth factor beta-1 (TGF-β1). Beck depression inventory questionnaire was used to report depressive symptoms. Data were statistically analyzed by paired and unpaired student's t-test, and Chi-square test. A total number of 44 patients completed the study. The two groups were statistically similar at baseline. After treatment and as compared to baseline data and placebo, montelukast showed a statistically significant improvement in liver stiffness, liver enzymes, metabolic parameters (except LDL-C), TNF-α, 8-OHdG, and liver fibrosis biomarkers (HA and TGF-β1). Furthermore, montelukast was well tolerated and didn't provoke depression. In this proof-of-concept study, treatment with montelukast may represent a promising therapeutic strategy for patients with non-alcoholic steatohepatitis secondary to its efficacy and safety. Clinicaltrial.gov ID: NCT04080947.
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Affiliation(s)
- Mahmoud Samy Abdallah
- Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City (USC), Sadat City, Menoufia, 32897, Egypt.
| | - Ahmed Hossam Eldeen
- Department of Hepatology, National Liver Institute, Menoufia University, Egypt.
| | - Sally Said Tantawy
- Shebin El-Kom Hospital of Fever, Gastrointestinal and Hepatic Diseases, Menoufia, Egypt.
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21
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Rupcic Rubin V, Bojanic K, Smolic M, Rubin J, Tabll A, Smolic R. An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents. J Clin Transl Hepatol 2021. [PMID: 33604256 DOI: 10.14218/jcth.2020.00040.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents.
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Affiliation(s)
- Vinka Rupcic Rubin
- Department of Gynaecology and Obstetrics, Osijek University Hospital Centre, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Kristina Bojanic
- Department of Biophysics and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Radiology, Health Center Osijek, Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jurica Rubin
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
| | - Ashraf Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, Egypt.,Department of immunology, Egypt Center for Research and Regenerative
| | - Robert Smolic
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia.,Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
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22
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Rupcic Rubin V, Bojanic K, Smolic M, Rubin J, Tabll A, Smolic R. An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents. J Clin Transl Hepatol 2021; 9:60-70. [PMID: 33604256 PMCID: PMC7868700 DOI: 10.14218/jcth.2020.00040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 11/22/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents.
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Affiliation(s)
- Vinka Rupcic Rubin
- Department of Gynaecology and Obstetrics, Osijek University Hospital Centre, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Kristina Bojanic
- Department of Biophysics and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Radiology, Health Center Osijek, Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jurica Rubin
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
| | - Ashraf Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, Egypt
- Department of immunology, Egypt Center for Research and Regenerative
| | - Robert Smolic
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
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23
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Christofides A, Konstantinidou E, Jani C, Boussiotis VA. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 2021; 114:154338. [PMID: 32791172 PMCID: PMC7736084 DOI: 10.1016/j.metabol.2020.154338] [Citation(s) in RCA: 362] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/06/2020] [Accepted: 07/24/2020] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.
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Affiliation(s)
- Anthos Christofides
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Eirini Konstantinidou
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Chinmay Jani
- Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Mt. Auburn Hospital, Cambridge, MA 02138, United States of America
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America.
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24
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Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020; 9:E1638. [PMID: 32650421 PMCID: PMC7408116 DOI: 10.3390/cells9071638] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Affiliation(s)
- Anne Fougerat
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Alexandra Montagner
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France
| | - Nicolas Loiseau
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Hervé Guillou
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Walter Wahli
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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25
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Treatments of nonalcoholic fatty liver disease in adults who have no other illness: A Review article. Arab J Gastroenterol 2019; 20:189-197. [DOI: 10.1016/j.ajg.2019.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 11/26/2019] [Indexed: 12/28/2022]
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Abstract
Introduction: Liver cirrhosis is the most deleterious consequence of chronic liver diseases of different etiologies. Progression of liver diseases to cirrhosis, irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response, sustained activation of fibrogenesis and wound-healing response. Despite intensive research on antifibrotic drugs, novel therapeutics specifically for liver have not been yet licensed. This review will examine compounds currently under development and key challenges in specific settings as for example that of NAFLD associated fibrosis.Areas covered: Results of the main phase II and III trial, including those with negative results, are presented and discussed. The endpoints selected and their limitations highlighted in order to suggest potential options to move forward.Expert opinion: Strategies based on single-molecule targets, associated so far with some disappointing results, may be unlikely to succeed in the context of such complex pathogenesis. Blocking at the same time different pathways that drive fibrosis progression may be required to provide significant benefit.
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Affiliation(s)
- Rosanna Santoro
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
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27
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Liu F, Bayliss G, Zhuang S. Application of nintedanib and other potential anti-fibrotic agents in fibrotic diseases. Clin Sci (Lond) 2019; 133:1309-1320. [PMID: 31217321 PMCID: PMC7480985 DOI: 10.1042/cs20190249] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/22/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022]
Abstract
Nintedanib, a Food and Drug Administration-approved drug for the treatment of patients with idiopathic pulmonary fibrosis (IPK), inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial growth factor receptors, and Src family kinases. Preclinical and clinical studies have revealed the potent anti-fibrotic effect of nintedanib in IPK in human and animal models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on the development and progression of tissue fibrosis in other organs, including liver, kidney, and skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial-mesenchymal transition, and suppression of inflammation and angiogenesis. In this article, we summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer our perspective about the possible clinical application of these agents in fibrotic diseases.
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Affiliation(s)
- Feng Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, U.S.A
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, U.S.A
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28
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Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019; 9:731-739. [PMID: 31889755 PMCID: PMC6926194 DOI: 10.1016/j.jceh.2019.06.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
| | | | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Address for correspondence: Dr. Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Sun XH, Zhang LD, Wei W. A study on the mechanism of adipokine in non-alcoholic fatty liver in rats treated by four herbs decoction. EUR J INFLAMM 2019. [DOI: 10.1177/2058739219853970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The objective of the study is to determine adipokine-associated mechanism of efficacy of Si He Decoction (SHD) for treating non-alcoholic fatty liver disease (NAFLD). Forty-five Sprague-Dawley (SD) rats were randomly divided into control group, model group, SHD low-dose group, SHD middle-dose group, and SHD high-dose group. Except control group, others were fed with a high-fat diet for 12 weeks to establish model. Then, H&E and oil red O staining were performed, and enzyme-linked immunosorbent assay (ELISA) was used to detect expression level of adipokine-associated molecules. H&E and oil red O staining results revealed that SHD treatment for NAFLD could effectively improve liver pathological conditions compared to that in model group, and the best efficacy was observed in SHD high-dose group. Compared to model group, SHD treatment could effectively downregulate expression level of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and upregulate expression level of visfatin, adiponectin (APN), leptin (LEP), and resistin in NAFLD rats. SHD can improve NAFLD through multiple means of targeting adipokines.
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Affiliation(s)
- Xiao-Hong Sun
- Department of Gastroenterology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Liang-Deng Zhang
- Chinese Medical Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Wei Wei
- Department of Gastroenterology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Sridharan K, Sivaramakrishnan G, Sequeira RP, Elamin A. Pharmacological interventions for non-alcoholic fatty liver disease: a systematic review and network meta-analysis. Postgrad Med J 2018; 94:556-565. [PMID: 30341231 DOI: 10.1136/postgradmedj-2018-135967] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 08/28/2018] [Accepted: 09/15/2018] [Indexed: 12/14/2022]
Abstract
AIM Several drugs have been used for treating non-alcoholic fatty liver disease (NAFLD). The present study is a network meta-analysis of such drugs. DESIGN, SETTING AND PATIENTS Randomised clinical trials comparing drug interventions in patients with NAFLD were analysed. OR and weighted mean difference (95 % CI) were the effect estimates for categorical and numerical outcomes, respectively. Random-effects model was used to generate pooled estimates. Surface under the cumulative ranking curve was used to rank the treatments. MAIN OUTCOME MEASURES Proportion of responders was the primary outcome measure and non-alcoholic steatohepatitis scores, liver enzymes, lipid profile, body mass index, homeostatic model assessment of insulin resistance, intrahepatic fat and adverse events were the key secondary outcomes. RESULTS 116 studies were included in the systematic review and 106 in the meta-analysis. Elafibranor, gemfibrozil, metadoxine, obeticholic acid, pentoxifylline, pioglitazone, probiotics, telmisartan, vildagliptin and vitamin E significantly increased the response rate than standard of care. Various other drugs were observed to modify the secondary outcomes favourably. Probiotics was found with a better response in children; and elafibranor, obeticholic acid, pentoxifylline and pioglitazone in patients with type 2 diabetes mellitus. The quality of evidence observed was either low or very low. CONCLUSION In patients with NAFLD, several drugs have been shown to have variable therapeutic benefit. However, the estimates and the inferences should be considered with extreme caution as it might change with the advent of future head-to-head clinical trials.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Gowri Sivaramakrishnan
- School of Oral Health, College of Medicine, Nursing and Health Sciences, Fiji National University, Suva, Fiji
| | - Reginald Paul Sequeira
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Abdelaziz Elamin
- Department of Pediatrics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
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Investigating Pathogenic and Hepatocarcinogenic Mechanisms from Normal Liver to HCC by Constructing Genetic and Epigenetic Networks via Big Genetic and Epigenetic Data Mining and Genome-Wide NGS Data Identification. DISEASE MARKERS 2018; 2018:8635329. [PMID: 30344796 PMCID: PMC6174771 DOI: 10.1155/2018/8635329] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 08/02/2018] [Accepted: 08/13/2018] [Indexed: 12/14/2022]
Abstract
The prevalence of hepatocellular carcinoma (HCC) is still high worldwide because liver diseases could develop into HCC. Recent reports indicate nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD&NASH) and primary biliary cirrhosis and primary sclerosing cholangitis (PBC&PSC) are significant of HCC. Therefore, understanding the cellular mechanisms of the pathogenesis and hepatocarcinogenesis from normal liver cells to HCC through NAFLD&NASH or PBC&PSC is a priority to prevent the progression of liver damage and reduce the risk of further complications. By the genetic and epigenetic data mining and the system identification through next-generation sequencing data and its corresponding DNA methylation profiles of liver cells in normal, NAFLD&NASH, PBC&PSC, and HCC patients, we identified the genome-wide real genetic and epigenetic networks (GENs) of normal, NAFLD&NASH, PBC&PSC, and HCC patients. In order to get valuable insight into these identified genome-wide GENs, we then applied a principal network projection method to extract the corresponding core GENs for normal liver cells, NAFLD&NASH, PBC&PSC, and HCC. By comparing the signal transduction pathways involved in the identified core GENs, we found that the hepatocarcinogenesis through NAFLD&NASH was induced through DNA methylation of HIST2H2BE, HSPB1, RPL30, and ALDOB and the regulation of miR-21 and miR-122, and the hepatocarcinogenesis through PBC&PSC was induced through DNA methylation of RPL23A, HIST2H2BE, TIMP1, IGF2, RPL30, and ALDOB and the regulation of miR-29a, miR-21, and miR-122. The genetic and epigenetic changes in the pathogenesis and hepatocarcinogenesis potentially serve as potential diagnostic biomarkers and/or therapeutic targets.
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Cao YN, Baiyisaiti A, Wong CW, Hsu SH, Qi R. Polyurethane Nanoparticle-Loaded Fenofibrate Exerts Inhibitory Effects on Nonalcoholic Fatty Liver Disease in Mice. Mol Pharm 2018; 15:4550-4557. [PMID: 30188729 DOI: 10.1021/acs.molpharmaceut.8b00548] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Polyurethane (PU) nanoparticles are potential drug carriers. We aimed to study the in vitro and in vivo efficacy of biodegradable PU nanoparticles loaded with fenofibrate (FNB-PU) on nonalcoholic fatty liver disease (NAFLD). FNB-PU was prepared by a green process, and its preventive effects on NAFLD were investigated on HepG2 cells and mice. FNB-PU showed sustained in vitro FNB release profile. Compared to FNB crude drug, FNB-PU significantly decreased triglyceride content in HepG2 cells incubated with oleic acid and in livers of mice with NAFLD induced by a methionine choline deficient diet, and increased plasma FNB concentration of the mice. FNB-PU increased absorption of FNB and therefore enhanced the inhibitory effects of FNB on NAFLD.
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Affiliation(s)
- Yi-Ni Cao
- Peking University Institute of Cardiovascular Sciences , Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems , Beijing , China
| | - Asiya Baiyisaiti
- School of Pharmacy , Shihezi University , Shihezi , Xinjiang , China
| | - Chui-Wei Wong
- Institute of Polymer Science and Engineering , National Taiwan University , Taipei , Taiwan
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering , National Taiwan University , Taipei , Taiwan
| | - Rong Qi
- Peking University Institute of Cardiovascular Sciences , Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems , Beijing , China
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Silva AKS, Peixoto CA. Role of peroxisome proliferator-activated receptors in non-alcoholic fatty liver disease inflammation. Cell Mol Life Sci 2018; 75:2951-2961. [PMID: 29789866 PMCID: PMC11105365 DOI: 10.1007/s00018-018-2838-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 04/13/2018] [Accepted: 05/07/2018] [Indexed: 02/07/2023]
Abstract
Overweight and obesity have been identified as the most important risk factors for many diseases, including cardiovascular disease, type 2 diabetes and lipid disorders, such as non-alcoholic fatty liver disease (NAFLD). The metabolic changes associated with obesity are grouped to define metabolic syndrome, which is one of the main causes of morbidity and mortality in industrialized countries. NAFLD is considered to be the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver diseases worldwide. Inflammation plays an important role in the development of numerous liver diseases, contributing to the progression to more severe stages, such as non-alcoholic steatohepatitis and hepatocellular carcinoma. Peroxisome proliferator-activated receptors (PPARs) are binder-activated nuclear receptors that are involved in the transcriptional regulation of lipid metabolism, energy balance, inflammation and atherosclerosis. Three isotypes are known: PPAR-α, PPARδ/β and PPAR-γ. These isotypes play different roles in diverse tissues and cells, including the inflammatory process. In this review, we discuss current knowledge on the role PPARs in the hepatic inflammatory process involved in NAFLD as well as new pharmacological strategies that target PPARs.
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Affiliation(s)
- Amanda Karolina Soares Silva
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Avenida Professor Moraes Rego, s/n, Cidade Universitária, Recife, PE, 50670-420, Brazil
- Biological Sciences of the Federal University of Pernambuco, Recife, PE, Brazil
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Avenida Professor Moraes Rego, s/n, Cidade Universitária, Recife, PE, 50670-420, Brazil.
- Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil.
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Kosmalski M, Mokros Ł, Kuna P, Witusik A, Pietras T. Changes in the immune system - the key to diagnostics and therapy of patients with non-alcoholic fatty liver disease. Cent Eur J Immunol 2018; 43:231-239. [PMID: 30135638 PMCID: PMC6102613 DOI: 10.5114/ceji.2018.77395] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 06/12/2017] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common pathologies of that organ. The development of the disease involves a variety of mechanisms, including insulin resistance, oxidative stress, endoplasmic reticulum stress, endotoxins from the intestinal flora and genetic predispositions. Additionally, clinical data suggest that the presence of NAFLD is associated with excessive activation of the immune system. For practical purposes, attention should be paid to the moment when the subjects predisposed to NAFLD develop inflammatory infiltration and signs of fibrosis in the liver (non-alcoholic steatohepatitis - NASH). Their presence is an important risk factor for hepatic cirrhosis, hepatic failure, and hepatocellular carcinoma, as well as for the occurrence of cardiovascular events. Regardless of the diagnostic methods used, including laboratory tests and imaging, liver biopsy remains the gold standard to identify and differentiate patients with NAFLD and NASH. The search for other, safer, cheaper and more readily available diagnostic tests is still being continued. Attention has been drawn to the usefulness of markers of immune status of the organism, not only for the diagnosis of NASH, but also for the identification of NAFLD patients at risk of disease progression. Despite the effectiveness of medication, no recommendations have been established for pharmacotherapy of NAFLD. Data indicate the primary need for non-pharmacological interventions to reduce body weight. However, there is evidence of the applicability of certain drugs and dietary supplements, which, by their effect on the immune system, inhibit its excessive activity, thus preventing the progression of NAFLD to NASH.
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Affiliation(s)
- Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
| | - Łukasz Mokros
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
| | - Piotr Kuna
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Poland
| | - Andrzej Witusik
- Department of Psychology, Piotrków Trybunalski Branch, Jan Kochanowski University in Kielce, Poland
| | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, Poland
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35
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Eshraghian A. Current and emerging pharmacological therapy for non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:7495-7504. [PMID: 29204050 PMCID: PMC5698243 DOI: 10.3748/wjg.v23.i42.7495] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
The main treatment of patients with non-alcoholic fatty liver disease (NAFLD) is life style modification including weight reduction and dietary regimen. Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis (NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.
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Affiliation(s)
- Ahad Eshraghian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71937-11351, Iran
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36
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Tang JT, Mao YM. Pharmacotherapy of nonalcoholic steatohepatitis: Reflections on the existing evidence. J Dig Dis 2017; 18:607-617. [PMID: 29106066 DOI: 10.1111/1751-2980.12557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/05/2017] [Accepted: 10/29/2017] [Indexed: 12/11/2022]
Abstract
Pharmacotherapy for nonalcoholic fatty liver disease (NAFLD) has not yet been approved by the US Food and Drug Administration. Over the past decade, a large number of clinical studies have explored the safety and efficacy of different drugs in treating nonalcoholic steatohepatitis (NASH), including diet pills, antioxidants, insulin sensitizers, lipid-lowering agents, anti-inflammatory cytokines, cytoprotective agents and intestinal probiotics. Based on the evidence from randomized controlled trials a number of academic groups have developed guidelines for the diagnosis and management of NAFLD and NASH. In this article, we discussed the current situation of NASH pharmacotherapy.
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Affiliation(s)
- Jie Ting Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yi Min Mao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
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Abstract
Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.
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Affiliation(s)
- Benita L McVicker
- Research Service, VA Nebraska-Western Iowa Health Care System, OmahaNE, United States.,Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, OmahaNE, United States
| | - Robert G Bennett
- Research Service, VA Nebraska-Western Iowa Health Care System, OmahaNE, United States.,The Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, OmahaNE, United States.,Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, OmahaNE, United States
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38
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Sun X, Zhang Y, Xie M. Review. The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease. ACTA PHARMACEUTICA 2017; 67:1-13. [PMID: 28231052 DOI: 10.1515/acph-2017-0007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/06/2016] [Indexed: 12/24/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD. Many drugs developed so far are targeted at PPARs. Thus, the aim of this paper is to summarize the roles of PPARs in the treatment of NAFLD.
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Affiliation(s)
- Xin Sun
- Department of Pharmacy Wuxi No. 2 People´s Hospital The Affiliated Hospital of Nanjing Medical University , Wuxi , Jiangsu 214002, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, The Affiliated Hospital of Nanjing Medical University , Wuxi , Jiangsu, 214002, China
- Department of Pharmacology College of Pharmaceutical Sciences Soochow University , Suzhou , Jiangsu 215123, China
| | - Meilin Xie
- Department of Pharmacology College of Pharmaceutical Sciences Soochow University , Suzhou , Jiangsu 215123, China
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Brie D, Sahebkar A, Penson PE, Dinca M, Ursoniu S, Serban MC, Zanchetti A, Howard G, Ahmed A, Aronow WS, Muntner P, Lip GYH, Wong ND, Rysz J, Banach M. Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hypertens 2016; 34:2318-2329. [PMID: 27512972 DOI: 10.1097/hjh.0000000000001086] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Pentoxifylline is a xanthine derivative with potential cardiovascular benefits. AIM To evaluate the impact of pentoxifylline on blood pressure (BP) and plasma TNF-α, C-reactive protein (CRP) and IL-6 through a systematic review and meta-analysis of randomized controlled trials. METHODS The protocol was registered (PROSPERO: CRD42016035988). The search included PUBMED, ProQuest, Scopus and EMBASE until 1 September 2015 to identify trials reporting BP or inflammatory markers during pentoxifylline therapy. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WDF) and 95% confidence intervals (CIs) as summary statistics. RESULTS Fifteen studies (16 treatment arms) were found to be eligible for inclusion. Meta-analysis did not suggest any effect of pentoxifylline on either SBP or DBP. Pentoxifylline treatment was associated with a significant reduction in plasma concentrations of TNF-α (WDF: -1.03 pg/ml, 95% CI: -1.54, -0.51; P < 0.001, 11 treatment arms) and CRP (WDF: -1.39 mg/l, 95% CI: -2.68, -0.10; P = 0.034, five treatment arms). No alteration in plasma IL-6 concentration was observed. The impact of pentoxifylline on plasma TNF-α levels was found to be positively associated with treatment duration (slope: 0.031; 95% CI: 0.004, 0.057; P = 0.023) but independent of pentoxifylline dose (slope: -0.0003; 95% CI: -0.002, 0.001; P = 0.687). CONCLUSION Pentoxifylline did not alter BP or plasma IL-6 concentration, but significantly reduced circulating TNF-α and CRP concentrations.
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Affiliation(s)
- Daniel Brie
- aInstitute for Cardiovascular Medicine Timisoara, Cardiology Department, University of Medicine and Pharmacy 'Victor Babes', Timisoara, Romania bBiotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran cMetabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia dSchool of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK eIndependent Pharmacist Researcher, Leuven, Belgium fDepartment of Functional Sciences, Discipline of Public Health, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania gDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA hDepartment of Functional Sciences, Discipline of Pathophysiology, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania iIstituto Auxologico Italiano, University of Milan, Milan, Italy jDepartment of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA kVeterans Affairs Medical Center, Washington, District of Columbia lDepartment of Medicine, New York Medical College, Valhalla, New York, USA mUniversity of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK nDivision of Cardiology, Heart Disease Prevention Program, University of California, Irvine, California, USA oChair of Nephrology and Hypertension pDepartment of Hypertension, Chair of Nephrology and Hypertension, Medical University of Łódź, Łódź, Poland
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Abdulla A, Reynolds C, Hesham A-Kader H. Non-Alcoholic Fatty Liver Disease (NAFLD): The Search for a Cure. EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10314771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
An alarming rise of obesity and, along with it, non-alcoholic fatty liver disease (NAFLD), has been observed in the USA and the rest of the world. NAFLD, the most common cause of chronic liver disease in many developed countries, is not always a benign disorder and considering its growing nature, will have a serious impact on healthcare systems worldwide. The search continues for a suitable therapy for this disorder; the therapy ideally needs to be safe, effective, and affordable. The biggest hurdle in the process of developing such a therapy is our lack of a complete understanding of the pathogenesis of the disease.
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Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther 2016; 33:291-319. [PMID: 26921205 DOI: 10.1007/s12325-016-0306-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
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Affiliation(s)
| | - Fabio Nascimbeni
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
- University of Modena and Reggio Emilia, Modena, Italy
| | - Dante Romagnoli
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
| | | | - Amedeo Lonardo
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.
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