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Wang L, Zhang C, Ma J, Li J, Wu Y, Ren Y, Li J, Li Y, Yang Y. Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease. Eur J Med Res 2025; 30:296. [PMID: 40247356 PMCID: PMC12004885 DOI: 10.1186/s40001-025-02557-9] [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: 01/13/2025] [Accepted: 04/04/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in modulating intrahepatic lipid homeostasis, suggesting its therapeutic potential for non-alcoholic fatty liver disease (NAFLD) management. This investigation seeks to elucidate the pathophysiological mechanisms through which MST1 modulates NASH progression. METHODS The experimental design employed two murine genetic models-wild-type (WT) controls and MST1-knockout (MST1-KO) specimens-subjected to a nutritionally modified Western diet (WD) enriched with saturated fats, simple carbohydrates, and dietary cholesterol to induce non-alcoholic steatohepatitis (NASH) pathogenesis. Lentiviral transduction techniques facilitated targeted MST1 overexpression in WT animals maintained on this dietary regimen. Parallel in vitro investigations utilized HepG2 hepatocyte cultures exposed to free fatty acid (FFA) cocktails comprising palmitic and oleic acids, coupled with CRISPR-mediated MST1 suppression and complementary gain-of-function manipulations to delineate molecular mechanisms. RESULTS NASH triggers hepatic sterol biosynthesis activation, resulting in pathological FC overload concurrent with MST1 transcriptional suppression. Genetic ablation of MST1 amplifies intrahepatic FC retention and potentiates histopathological inflammation, while MST1 reconstitution mitigates steatotic FC deposition and attenuates inflammatory cascades. Mechanistic profiling revealed MST1-mediated AMPKα phosphorylation at Thr172, which suppresses cholesterogenic enzyme expression via sterol regulatory element-binding transcription factor 2 (SREBP2) axis modulation. This phosphorylation cascade demonstrates dose-dependent inhibition of HMGCR activity, resolving FC-induced hepatotoxicity. Crucially, MST1 orchestrates AMPK/SREBP2 crosstalk to maintain sterol homeostasis, with knockout models exhibiting 67% elevated SREBP2 nuclear translocation compared to controls. CONCLUSIONS The regulatory axis involving MST1-mediated AMPK phosphorylation emerges as a promising therapeutic modality for modulating hepatic sterol metabolism. It demonstrates significant potential in arresting the progression of inflammatory cascades and extracellular matrix remodeling characteristic of NASH pathogenesis. Mechanistic studies confirm that this phosphorylation cascade effectively suppresses de novo lipogenesis while enhancing cholesterol efflux capacity, thereby establishing a dual-target strategy against both metabolic dysfunction and fibrotic transformation in preclinical models.
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Affiliation(s)
- Lijuan Wang
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China
| | - Chenglei Zhang
- Medical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China
| | - Jie Ma
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China
| | - Jiarui Li
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China
| | - Yuanyuan Wu
- Department of Oncology, Cancer Hospital, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China
| | - Yanru Ren
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China
| | - Jianning Li
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China
| | - Yan Li
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China.
| | - Yi Yang
- School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan, 750001, Ningxia, China.
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Zisis M, Chondrogianni ME, Androutsakos T, Rantos I, Oikonomou E, Chatzigeorgiou A, Kassi E. Linking Cardiovascular Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): The Role of Cardiometabolic Drugs in MASLD Treatment. Biomolecules 2025; 15:324. [PMID: 40149860 PMCID: PMC11940321 DOI: 10.3390/biom15030324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/29/2025] Open
Abstract
The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.
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Affiliation(s)
- Marios Zisis
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Ilias Rantos
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Li Q, Sheng J, Baruscotti M, Liu Z, Wang Y, Zhao L. Identification of Senkyunolide I as a novel modulator of hepatic steatosis and PPARα signaling in zebrafish and hamster models. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118743. [PMID: 39209000 DOI: 10.1016/j.jep.2024.118743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/19/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.
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Affiliation(s)
- Qingquan Li
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jian Sheng
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mirko Baruscotti
- Department of Biosciences, University of Milano, Milan, 1-20133, Italy
| | - Zhenjie Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310020, China
| | - Lu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China; State Key Laboratory of Chinese Medicine Modernization, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Jiao B, Wang B, Liu B, Zhao J, Zhang Y. Potential impact of ezetimibe on patients with NAFLD/NASH: a meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2024; 15:1468476. [PMID: 39439571 PMCID: PMC11493694 DOI: 10.3389/fendo.2024.1468476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/20/2024] [Indexed: 10/25/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease. Studies have found that ezetimibe may be utilized as a supplemental treatment for NAFLD. Additionally, many clinical trials reported the potential impacts of ezetimibe on patients with NAFLD, although some conclusions remain controversial. Therefore, this study aimed to evaluate the effects of ezetimibe on patients with NAFLD. Method Online search was conducted across databases including PubMed, Embase, Scopus, Web of Science, Cochrane Library, Wanfang, VIP, and CNKI to retrieve all relevant controlled studies on the treatment of NAFLD with ezetimibe from the inception of the databases until April 2024. This meta-analysis comprised 10 randomized controlled trials (RCTs). Statistical analysis was conducted using the Meta package in R v4.3.2. Results A total of ten RCTs were included in this study, encompassing 578 patients (290 in the ezetimibe group and 288 in the control group) diagnosed with NAFLD/non-alcoholic steatohepatitis (NASH). The results indicated that ezetimibe significantly reduced levels of aspartate aminotransferase (P < 0.01), glutamyl transferase (γ-GT) (P < 0.01), total cholesterol (P < 0.01), low-density lipoprotein cholesterol (P < 0.01), high-sensitivity C-reactive protein (P < 0.01), and interleukin-6 (P < 0.01), and markedly increased levels of glycated hemoglobin (P = 0.02). Conclusions Ezetimibe may partially improve transaminase levels and positively impact liver function in patients with NAFLD/NASH. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023461467.
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Zhang YY, Chen BX, Wan Q. Association of lipid-lowering drugs with the risk of type 2 diabetes and its complications: a mendelian randomized study. Diabetol Metab Syndr 2024; 16:240. [PMID: 39367514 PMCID: PMC11451088 DOI: 10.1186/s13098-024-01477-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/23/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND The pathogenesis of type 2 diabetes mellitus is somewhat associated with lipid metabolism. We aim to assess the impact of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) on type 2 diabetes mellitus and its complications through a two-sample Mendelian randomization (MR) study. METHOD We identified suitable genetic instruments from the GWAS database that represent the expression levels of three genes, interpreting reduced genetically proxied gene expression as indicative of lipid-lowering drug use. We evaluated the causal relationships among these variables employing a two-sample Mendelian randomization approach, with the Inverse Variance Weighted (IVW) analysis serving as the primary method. Coronary artery disease was utilized as a positive control to validate the reliability of the selected genetic instruments. RESULT Increased genetically proxied HMGCR expression is significantly associated with a reduced risk of type 2 diabetes mellitus (OR = 0.64, 95%CI = 0.55-0.74), which was replicated in the FinnGen study with consistent results (OR = 0.65, 95%CI = 0.53-0.80). Increased genetically proxied HMGCR expression is associated with a reduced risk of diabetic retinopathy (OR = 0.23, 95%CI = 0.12-0.44) and diabetic nephropathy (OR = 0.35, 95%CI = 0.17-0.71). In contrast, increased genetically proxied PCSK9 expression is associated with a decreased risk of diabetic coma (OR = 0.70, 95%CI = 0.50-0.98), diabetic neuropathy (OR = 0.24, 95%CI = 0.14-0.42), diabetic retinopathy (OR = 0.67, 95%CI = 0.48-0.96), diabetic cardiovascular diseases (OR = 0.62, 95%CI = 0.38-0.99), and diabetic nephropathy (OR = 0.62, 95%CI = 0.41-0.95). CONCLUSIONS This Mendelian randomization study suggests an association between HMGCR and the pathogenesis of type 2 diabetes mellitus, with increased genetically proxied HMGCR expression reducing the risk of type 2 diabetes mellitus, while PCSK9 and NPC1L1 show no significant association with type 2 diabetes mellitus. These findings may offer more reasonable lipid-lowering drug options for patients with dyslipidemia.
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Affiliation(s)
- Yue-Yang Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China
| | - Bing-Xue Chen
- Department of Ultrasound Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qin Wan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China.
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China.
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Tang S, Borlak J. Genomics of human NAFLD: Lack of data reproducibility and high interpatient variability in drug target expression as major causes of drug failures. Hepatology 2024; 80:901-915. [PMID: 38358517 PMCID: PMC11407777 DOI: 10.1097/hep.0000000000000780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND AND AIMS NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail. To better comprehend drug failures, we investigated the reproducibility of fatty liver genomic data across 418 liver biopsies and evaluated the interpatient variability of 18 drug targets. APPROACH AND RESULTS Apart from our own data, we retrieved NAFLD biopsy genomic data sets from public repositories and considered patient demographics. We divided the data into test and validation sets, assessed the reproducibility of differentially expressed genes and performed gene enrichment analysis. Patients were stratified by disease activity score, fibrosis grades and sex, and we investigated the regulation of 18 drug targets across 418 NAFLD biopsies of which 278 are NASH cases. We observed poor reproducibility of differentially expressed genes across 9 independent studies. On average, only 4% of differentially expressed genes are commonly regulated based on identical sex and 2% based on identical NAS disease score and fibrosis grade. Furthermore, we observed sex-specific gene regulations, and for females, we noticed induced expression of genes coding for inflammatory response, Ag presentation, and processing. Conversely, extracellular matrix receptor interactions are upregulated in males, and the data agree with clinical findings. Strikingly, and with the exception of stearoyl-CoA desaturase, most drug targets are not regulated in > 80% of patients. CONCLUSIONS Lack of data reproducibility, high interpatient variability, and the absence of disease-dependent drug target regulations are likely causes of NASH drug failures in clinical trials.
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Yang H, Suh DH, Jung ES, Lee Y, Liu KH, Do IG, Lee CH, Park CY. Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation. Front Pharmacol 2024; 15:1406493. [PMID: 38953111 PMCID: PMC11215075 DOI: 10.3389/fphar.2024.1406493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/13/2024] [Indexed: 07/03/2024] Open
Abstract
Background Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis. Methods We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism. Results In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3. Conclusion This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.
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Affiliation(s)
- Hyekyung Yang
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Ho Suh
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Eun Sung Jung
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Yoonjin Lee
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kwang-Hyeon Liu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Cheol-Young Park
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Raggi P, Milic J, Manicardi M, Cinque F, Swain MG, Sebastiani G, Guaraldi G. Metabolic dysfunction-associated steatotic liver disease: An opportunity for collaboration between cardiology and hepatology. Atherosclerosis 2024; 392:117523. [PMID: 38522165 DOI: 10.1016/j.atherosclerosis.2024.117523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/07/2024] [Accepted: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Altered metabolic function has many detrimental effects on the body that can manifest as cardiovascular and liver diseases. Traditional approaches to understanding and treating metabolic dysfunction-associated disorders have been organ-centered, leading to silo-type disease care. However, given the broad impact that systemic metabolic dysfunction has on the human body, approaches that simultaneously involve multiple medical specialists need to be developed and encouraged to optimize patient outcomes. In this review, we highlight how several of the treatments developed for cardiac care may have a beneficial effect on the liver and vice versa, suggesting that there is a need to target the disease process, rather than specifically target the cardiovascular or liver specific sequelae of metabolic dysfunction.
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Affiliation(s)
- Paolo Raggi
- Department of Medicine and Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
| | - Jovana Milic
- Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy
| | - Marcella Manicardi
- Cardiology Department, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
| | - Felice Cinque
- SC-Medicina Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan, Department of Pathophysiology and Transplantation, University of Milan, Italy; Division of Gastroenterology and Hepatology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada
| | - Mark G Swain
- Department of Medicine, University of Calgary Liver Unit, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Giovanni Guaraldi
- Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy; Department of Infectious Diseases, Azienda Ospedaliero-Universitaria, Policlinico of Modena, Modena, Italy
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Li M, Zhang W, Zhang M, Li L, Wang D, Yan G, Qiao Y, Tang C. Nonlinear relationship between untraditional lipid parameters and the risk of prediabetes: a large retrospective study based on Chinese adults. Cardiovasc Diabetol 2024; 23:12. [PMID: 38184606 PMCID: PMC10771669 DOI: 10.1186/s12933-023-02103-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 12/25/2023] [Indexed: 01/08/2024] Open
Abstract
BACKGROUND Abnormal lipid metabolism poses a risk for prediabetes. However, research on lipid parameters used to predict the risk of prediabetes is scarce, and the significance of traditional and untraditional lipid parameters remains unexplored in prediabetes. This study aimed to comprehensively evaluate the association between 12 lipid parameters and prediabetes and their diagnostic value. METHODS This cross-sectional study included data from 100,309 Chinese adults with normal baseline blood glucose levels. New onset of prediabetes was the outcome of concern. Untraditional lipid parameters were derived from traditional lipid parameters. Multivariate logistic regression and smooth curve fitting were used to examine the nonlinear relationship between lipid parameters and prediabetes. A two-piecewise linear regression model was used to identify the critical points of lipid parameters influencing the risk of prediabetes. The areas under the receiver operating characteristic curve estimated the predictive value of the lipid parameters. RESULTS A total of 12,352 participants (12.31%) were newly diagnosed with prediabetes. Following adjustments for confounding covariables, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol were negatively correlated with prediabetes risk. Conversely, total cholesterol, triglyceride (TG), lipoprotein combine index (LCI), atherogenic index of plasma (AIP), non-HDL-C, atherogenic coefficient, Castelli's index-I, remnant cholesterol (RC), and RC/HDL-C ratio displayed positive correlations. In younger adults, females, individuals with a family history of diabetes, and non-obese individuals, LCI, TG, and AIP exhibited higher predictive values for the onset of prediabetes compared to other lipid profiles. CONCLUSION Nonlinear associations were observed between untraditional lipid parameters and the risk of prediabetes. The predictive value of untraditional lipid parameters for prediabetes surpassed that of traditional lipid parameters, with LCI emerging as the most effective predictor for prediabetes.
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Affiliation(s)
- Mingkang Li
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Wenkang Zhang
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Minhao Zhang
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Linqing Li
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Dong Wang
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Gaoliang Yan
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China
| | - Yong Qiao
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China.
| | - Chengchun Tang
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, China.
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Lee J, Lee SH. Expanding the therapeutic landscape: ezetimibe as non-statin therapy for dyslipidemia. Korean J Intern Med 2023; 38:797-809. [PMID: 37866817 PMCID: PMC10636547 DOI: 10.3904/kjim.2023.243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/21/2022] [Accepted: 09/13/2023] [Indexed: 10/24/2023] Open
Abstract
Dyslipidemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), and statins are the primary therapeutic options for reducing low-density lipoprotein cholesterol (LDL-C) levels. However, it can be challenging to achieve optimal LDL-C goals with statin monotherapy. Ezetimibe, a cholesterol absorption inhibitor, offers a potential non-statin therapy to optimize LDL-C management. Key clinical trials, such as IMPROVE-IT and RACING, have demonstrated that the addition of ezetimibe to statin therapy leads to further decreases in LDL-C or significant decreases in major adverse cardiovascular events (MACEs), particularly in patients with high ASCVD risk. Subsequent meta-analyses and clinical trials have further supported the beneficial effect of ezetimibe, suggesting additive decreases in LDL-C and MACEs, as well as pleiotropic effects. This review provides a comprehensive analysis of the clinical implications of ezetimibe for managing dyslipidemia; it also evaluates the available evidence that supports the role of ezetimibe as an adjunct non-statin therapy for long-term use. However, the long-term pleiotropic effects of ezetimibe remain controversial because of limited clinical data. Therefore, additional research is needed to clarify its potential benefits beyond LDL-C reduction. Nonetheless, an understanding of the role of ezetimibe in dyslipidemia management will help clinicians to develop effective treatment strategies.
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Affiliation(s)
- Jeongmin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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11
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Rajabian A, McCloskey AP, Jamialahmadi T, Moallem SA, Sahebkar A. A review on the efficacy and safety of lipid-lowering drugs in neurodegenerative disease. Rev Neurosci 2023; 34:801-824. [PMID: 37036894 DOI: 10.1515/revneuro-2023-0005] [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: 01/14/2023] [Accepted: 03/10/2023] [Indexed: 04/11/2023]
Abstract
There is a train of thought that lipid therapies may delay or limit the impact of neuronal loss and poor patient outcomes of neurodegenerative diseases (NDDs). A variety of medicines including lipid lowering modifiers (LLMs) are prescribed in NDDs. This paper summarizes the findings of clinical and observational trials including systematic reviews and meta-analyses relating to LLM use in NDDs published in the last 15 years thus providing an up-to-date evidence pool. Three databases were searched PubMed, CINAHL, and Web of Science using key terms relating to the review question. The findings confirm the benefit of LLMs in hyperlipidemic patients with or without cardiovascular risk factors due to their pleotropic effects. In NDDs LLMs are proposed to delay disease onset and slow the rate of progression. Clinical observations show that LLMs protect neurons from α-synuclein, tau, and Aβ toxicity, activation of inflammatory processes, and ultimately oxidative injury. Moreover, current meta-analyses and clinical trials indicated low rates of adverse events with LLMs when used as monotherapy. LLMs appear to have favorable safety and tolerability profiles with few patients stopping treatment due to severe adverse effects. Our collated evidence thus concludes that LLMs have a role in NDDs but further work is needed to understand the exact mechanism of action and reach more robust conclusions on where and when it is appropriate to use LLMs in NDDs in the clinic.
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Affiliation(s)
- Arezoo Rajabian
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alice P McCloskey
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK
| | - Tannaz Jamialahmadi
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, 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
| | - 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
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12
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Choe J, Lee SH, Ahn J, Lee H, Oh JH, Choi J, Lee H, Cha K, Park J. Effect of High-Intensity Rosuvastatin vs. Combination of Low-Intensity Rosuvastatin and Ezetimibe on HbA1c Levels in Patients without Diabetes: A Randomized IDEAL Trial. J Clin Med 2023; 12:6099. [PMID: 37763042 PMCID: PMC10532039 DOI: 10.3390/jcm12186099] [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: 07/13/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
There is a dearth of studies investigating whether the combination of low-intensity statins with ezetimibe can reduce the risk of diabetes in patients requiring statin therapy. Therefore, we aimed to evaluate the effects of combination therapy on the prevention of glycated hemoglobin (HbA1c) elevation in patients without diabetes. Sixty-eight patients were randomly assigned in a 1:1 ratio to receive a combination of low-intensity rosuvastatin (5 mg/day) and ezetimibe (10 mg/day) or high-intensity rosuvastatin (20 mg/day). The primary endpoint was the absolute difference in the HbA1c levels at 12 weeks. The HbA1c level showed an overall elevation of 0.11% at 12 weeks compared to that at baseline (mean ± standard deviation: 5.78 ± 0.3%, 95% confidence interval [CI]: 5.86-6.07, p = 0.044). The HbA1c levels did not differ between the groups at 12 weeks (least square mean difference: 0.001, 95% CI: 0.164-0.16, p = 0.999). Our study found that the combination of low-intensity rosuvastatin and ezetimibe did not yield significant differences in HbA1c levels compared to high-intensity rosuvastatin alone after 12 weeks in patients without diabetes. This suggests that the combination of low-intensity rosuvastatin and ezetimibe may not be an effective strategy for preventing HbA1c elevation in patients without diabetes requiring statins.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jinsup Park
- Department of Cardiology and Medical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.C.); (S.-H.L.); (J.A.); (H.L.); (J.-H.O.); (J.C.); (H.L.); (K.C.)
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13
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Kakiyama G, Rodriguez-Agudo D, Pandak WM. Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised "Two-Hit" Hypothesis. Cells 2023; 12:1434. [PMID: 37408268 PMCID: PMC10217489 DOI: 10.3390/cells12101434] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 07/07/2023] Open
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a well-known hallmark of early NAFLD progression, yet the mechanism linking aberrant insulin signaling to hepatocyte inflammation has remained unclear. Recently, as a function of more distinctly defining the regulation of mechanistic pathways, hepatocyte toxicity as mediated by hepatic free cholesterol and its metabolites has emerged as fundamental to the subsequent necroinflammation/fibrosis characteristics of NASH. More specifically, aberrant hepatocyte insulin signaling, as found with IR, leads to dysregulation in bile acid biosynthetic pathways with the subsequent intracellular accumulation of mitochondrial CYP27A1-derived cholesterol metabolites, (25R)26-hydroxycholesterol and 3β-Hydroxy-5-cholesten-(25R)26-oic acid, which appear to be responsible for driving hepatocyte toxicity. These findings bring forth a "two-hit" interpretation as to how NAFL progresses to NAFLD: abnormal hepatocyte insulin signaling, as occurs with IR, develops as a "first hit" that sequentially drives the accumulation of toxic CYP27A1-driven cholesterol metabolites as the "second hit". In the following review, we examine the mechanistic pathway by which mitochondria-derived cholesterol metabolites drive the development of NASH. Insights into mechanistic approaches for effective NASH intervention are provided.
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Affiliation(s)
- Genta Kakiyama
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
| | - Daniel Rodriguez-Agudo
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
| | - William M. Pandak
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
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14
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Yang G, Schooling CM. Statins, Type 2 Diabetes, and Body Mass Index: A Univariable and Multivariable Mendelian Randomization Study. J Clin Endocrinol Metab 2023; 108:385-396. [PMID: 36184662 DOI: 10.1210/clinem/dgac562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/22/2022] [Indexed: 01/20/2023]
Abstract
CONTEXT Statins and possibly other lipid modifiers increase type 2 diabetes risk and body mass index (BMI). However, to what extent BMI mediates the diabetogenic effects of lipid modifiers remains unclear. OBJECTIVE We used Mendelian randomization (MR) to investigate the effects of commonly used lipid modifiers on type 2 diabetes risk and glycemic traits, and any mediation by BMI. METHODS Using established genetic variants to mimic commonly used lipid modifiers (ie, statins, PCSK9 inhibitors, and ezetimibe), we assessed their associations with type 2 diabetes risk, glycated hemoglobin (HbA1c), fasting insulin, fasting glucose, and BMI in the largest relevant genome-wide association studies (GWAS) in people of European ancestry, and where possible, in East Asians. We used multivariable MR to examine the role of lipid modifiers independent of BMI. RESULTS Genetically mimicked effects of statins and ezetimibe, but not PCSK9 inhibitors were associated with higher risk of type 2 diabetes (odds ratio [OR] 1.74 [95% CI, 1.49 to 2.03]; 1.92 [1.22 to 3.02]; 1.06 [0.87 to 1.29] per SD reduction in low-density lipoprotein (LDL)-cholesterol). Of these lipid modifiers, only genetic mimics of statins were associated with higher BMI (0.33 SD [0.29 to 0.38] per SD reduction in LDL-cholesterol), which explained 54% of the total effect of statins on type 2 diabetes risk. CONCLUSION Higher BMI mediated more than half of the diabetogenic effects of statins, which did not extend to other commonly used lipid modifiers. Further investigations are needed to clarify drug-specific mechanisms underlying the effects of lipid modifiers on type 2 diabetes.
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Affiliation(s)
- Guoyi Yang
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - C Mary Schooling
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Graduate School of Public Health and Health Policy, City University of New York, New York 10027, USA
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15
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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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16
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Abdallah M, Brown L, Provenza J, Tariq R, Gowda S, Singal AK. Safety and efficacy of dyslipidemia treatment in NAFLD patients: a meta-analysis of randomized controlled trials. Ann Hepatol 2022; 27:100738. [PMID: 35781090 DOI: 10.1016/j.aohep.2022.100738] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES Practicing physicians often hesitate to use statins and/or other lipid-lowering therapies in NAFLD due to concern for hepatotoxicity. The aim of this study is to examine the safety of lipid lowering therapies in NAFLD patients. MATERIALS AND METHODS Data from randomized control trials (RCT) among NAFLD patients were pooled to examine the effect of lipid-lowering therapies on liver chemistry, lipid profile, and liver histology. Results are reported as the mean difference of the change (pretreatment-posttreatment) between the treatment and control group. RESULTS A total of 21 placebo-controlled RCT on 1900 patients (304 receiving statins, 520 other lipid-lowering therapies, and 61 combinations) were treated for 26 weeks [Interquartile range (IQR): 17.5-52 weeks]. Pooled data showed an improved lipid profile without any worsening of ALT, AST, total bilirubin, or alkaline phosphatase at the end of the treatment period. NAFLD activity score improved with other lipid-lowering agents but not with statins. There was no change in individual components of NAFLD activity score or fibrosis stage. CONCLUSION This meta-analysis of randomized controlled trials examining statins and/or other lipid-lowering therapies in NAFLD patients showed no evidence of worsening liver chemistry. Studies with longer use of lipid-lowering therapies are suggested to examine the benefit of liver histology among patients with NAFLD.
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Affiliation(s)
- Mohamed Abdallah
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States
| | - Landon Brown
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - John Provenza
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Raseen Tariq
- Department of Medicine, University of Rochester, NY, United States
| | - Smitha Gowda
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States
| | - Ashwani K Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States; Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, SD, United States.
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17
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Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2022; 45:2064-2075. [PMID: 35894933 PMCID: PMC9472500 DOI: 10.2337/dc21-2049] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/21/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noboru Takata
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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Duan Y, Gong K, Xu S, Zhang F, Meng X, Han J. Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Signal Transduct Target Ther 2022; 7:265. [PMID: 35918332 PMCID: PMC9344793 DOI: 10.1038/s41392-022-01125-5] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/04/2022] [Accepted: 07/12/2022] [Indexed: 12/13/2022] Open
Abstract
Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.
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Affiliation(s)
- Yajun Duan
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Ke Gong
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Suowen Xu
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Feng Zhang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Xianshe Meng
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. .,College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
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19
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Diabetes and Familial Hypercholesterolemia: Interplay between Lipid and Glucose Metabolism. Nutrients 2022; 14:nu14071503. [PMID: 35406116 PMCID: PMC9002616 DOI: 10.3390/nu14071503] [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: 03/04/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
Familial hypercholesterolemia (FH) is a genetic disease characterized by high low-density lipoprotein (LDL) cholesterol (LDL-c) concentrations that increase cardiovascular risk and cause premature death. The most frequent cause of the disease is a mutation in the LDL receptor (LDLR) gene. Diabetes is also associated with an increased risk of cardiovascular disease and mortality. People with FH seem to be protected from developing diabetes, whereas cholesterol-lowering treatments such as statins are associated with an increased risk of the disease. One of the hypotheses to explain this is based on the toxicity of LDL particles on insulin-secreting pancreatic β-cells, and their uptake by the latter, mediated by the LDLR. A healthy lifestyle and a relatively low body mass index in people with FH have also been proposed as explanations. Its association with superimposed diabetes modifies the phenotype of FH, both regarding the lipid profile and cardiovascular risk. However, findings regarding the association and interplay between these two diseases are conflicting. The present review summarizes the existing evidence and discusses knowledge gaps on the matter.
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20
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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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21
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Rong L, Zou J, Ran W, Qi X, Chen Y, Cui H, Guo J. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Front Endocrinol (Lausanne) 2022; 13:1087260. [PMID: 36726464 PMCID: PMC9884828 DOI: 10.3389/fendo.2022.1087260] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/28/2022] [Indexed: 01/17/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a series of diseases, involving excessive lipid deposition in the liver and is often accompanied by obesity, diabetes, dyslipidemia, abnormal blood pressure, and other metabolic disorders. In order to more accurately reflect its pathogenesis, an international consensus renamed NAFLD in 2020 as metabolic (dysfunction) associated with fatty liver disease (MAFLD). The changes in diet and lifestyle are recognized the non-drug treatment strategies; however, due to the complex pathogenesis of NAFLD, the current drug therapies are mainly focused on its pathogenic factors, key links of pathogenesis, and related metabolic disorders as targets. There is still a lack of specific drugs. In clinical studies, the common NAFLD treatments include the regulation of glucose and lipid metabolism to protect the liver and anti-inflammation. The NAFLD treatments based on the enterohepatic axis, targeting gut microbiota, are gradually emerging, and various new metabolism-regulating drugs are also under clinical development. Therefore, this review article has comprehensively discussed the research advancements in NAFLD treatment in recent years.
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Affiliation(s)
- Li Rong
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
| | - Junyan Zou
- Medical Research Institute, Southwest University, Chongqing, China
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Wei Ran
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Xiaohong Qi
- Department of General surgery, Baoshan People’s Hospital of Yunnan Province, Baoshan, Yunnan, China
| | - Yaokai Chen
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Hongjuan Cui
- Medical Research Institute, Southwest University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
- *Correspondence: Jinjun Guo,
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22
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Popovic DS, Papachristou S, Stokic E, Papanas N. Ezetimibe and Insulin Resistance. Curr Vasc Pharmacol 2022; 20:315-317. [PMID: 35232351 DOI: 10.2174/1570161120666220301140528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/30/2022] [Accepted: 01/30/2022] [Indexed: 01/25/2023]
Affiliation(s)
- Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia
- Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Stella Papachristou
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Edita Stokic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia
- Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
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23
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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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24
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Shi YW, He FP, Chen JJ, Deng H, Shi JP, Zhao CY, Mi YQ, Zou ZS, Zhou YJ, Di FS, Zheng RD, Du Q, Shang J, Yang RX, Popovic B, Zhong BH, Fan JG. Metabolic Disorders Combined with Noninvasive Tests to Screen Advanced Fibrosis in Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol 2021; 9:607-614. [PMID: 34722175 PMCID: PMC8516831 DOI: 10.14218/jcth.2021.00058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/30/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. METHODS A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. RESULTS Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004-5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083-9.725, p<0.001) were significantly associated with advanced fibrosis. Using these two metabolic disorders as a screening tool, a sensitivity, specificity and accuracy of 92%, 81% and 83% was achieved, respectively. With the new algorithms combining metabolic disorders with noninvasive measurements, the number of patients requiring liver biopsy was reduced, especially in combination with the Fibrosis-4 score and metabolic disorders (36% to 17%, p<0.001). In addition, this stepwise algorithm could achieve a high accuracy (85%) and high negative predictive value (93%). CONCLUSIONS Metabolic disorders should be taken into consideration in the diagnosis of advanced fibrosis. With further validation and investigation, new algorithms could be recommended in primary care units to spare patients from unnecessary referral and liver biopsies.
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Affiliation(s)
- Yi-Wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Fang-Ping He
- Department of Gastroenterology II, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Regions, Ürümqi, China
| | - Jin-Jun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hong Deng
- Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jun-Ping Shi
- The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Cai-Yan Zhao
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yu-Qiang Mi
- Department of Infectious Diseases, Tianjin Second People’s Hospital, Tianjin, China
| | - Zheng-Sheng Zou
- Department of Liver Disease, Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yong-Jian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Fu-Sheng Di
- Department of Endocrinology and Metabolism, The Third Central Hospital of Tianjin, Tianjin, China
| | - Rui-Dan Zheng
- Diagnosis and Treatment Center for Liver Diseases, Zhengxing Hospital, Zhangzhou, China
| | - Qin Du
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial Peoples’ Hospital Zhengzhou Zhengzhou, China
| | - Rui-Xu Yang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | | | - Bi-Hui Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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25
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Song Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metab 2021; 33:1911-1925. [PMID: 34562355 DOI: 10.1016/j.cmet.2021.09.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 12/23/2022]
Abstract
High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.
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Affiliation(s)
- Yongfeng Song
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong 250062, China
| | - Junjun Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong 250062, China
| | - Ke Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong 250062, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong 250062, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong 250062, China.
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26
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Sfikas G, Psallas M, Koumaras C, Imprialos K, Perdikakis E, Doumas M, Giouleme O, Karagiannis A, Athyros VG. Prevalence, Diagnosis, and Treatment with 3 Different Statins of Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis in Military Personnel. Do Genetics Play a Role? Curr Vasc Pharmacol 2021; 19:572-581. [DOI: 10.2174/1570161118666201015152921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 12/18/2022]
Abstract
Background:
Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic
steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in
the pathogenesis of NAFLD/NASH.
Aim:
To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate
the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity
Score (NAS); Fibrosis-4 score (FIB-4)].
Methods:
During the mandatory annual medical check-up, military personnel underwent a clinical
and laboratory evaluation. Participants with NAFLD/NASH were randomized into 4 groups
(n=151 each): diet-exercise, atorvastatin, rosuvastatin, or pitavastatin for 1 year (i.e., until the next
routine evaluation).
Results:
From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general
population, p<0.001), and a total of 604 consented to participate in the study. After a year of
treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline
vs. 5.62, p=0.07; FIB-4 3.42 vs. 3.52, p=0.7). For the atorvastatin group, both scores were reduced
(NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs
1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001,
FIB-4 3.78 vs 0.87, p<0.001).
Conclusions:
Atorvastatin, rosuvastatin, and pitavastatin have a beneficial and safe effect in
NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity)
and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/-
NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of
NAFLD/NASH and its treatment with statins.
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Affiliation(s)
- Georgios Sfikas
- 1st Department of Internal Medicine, 424 General Military Training Hospital, Thessaloniki, Greece
| | - Michael Psallas
- 1st Department of Internal Medicine, 424 General Military Training Hospital, Thessaloniki, Greece
| | - Charalambos Koumaras
- 1st Department of Internal Medicine, 424 General Military Training Hospital, Thessaloniki, Greece
| | - Konstantinos Imprialos
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Evangelos Perdikakis
- Department of Ultrasonography, 424 General Military Training Hospital, Thessaloniki, Greece
| | - Michael Doumas
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Olga Giouleme
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Asterios Karagiannis
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Vasilios G. Athyros
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University School of Medicine, Thessaloniki, Greece
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27
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Horn CL, Morales AL, Savard C, Farrell GC, Ioannou GN. Role of Cholesterol-Associated Steatohepatitis in the Development of NASH. Hepatol Commun 2021; 6:12-35. [PMID: 34558856 PMCID: PMC8710790 DOI: 10.1002/hep4.1801] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
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Affiliation(s)
- Christian L Horn
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Amilcar L Morales
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Christopher Savard
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Geoffrey C Farrell
- Liver Research Group, ANU Medical School, Australian National University at the Canberra Hospital, Garran, ACT, Australia
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
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28
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Kawaguchi K, Sakai Y, Terashima T, Shimode T, Seki A, Orita N, Takeshita Y, Shimakami T, Takatori H, Arai K, Kitamura K, Yamashita T, Yamashita T, Takamura M, Mizukoshi E, Takamura T, Honda M, Wada T, Kaneko S. Decline in serum albumin concentration is a predictor of serious events in nonalcoholic fatty liver disease. Medicine (Baltimore) 2021; 100:e26835. [PMID: 34397849 PMCID: PMC8341320 DOI: 10.1097/md.0000000000026835] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 06/20/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023] Open
Abstract
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which includes diabetes mellitus and hyperlipidemia. A fraction of NAFLD patients develop nonalcoholic steatohepatitis, leading to cirrhosis associated with various serious complications, including hepatocellular carcinoma, gastroesophageal varices, cardiovascular events, and other organ malignancy. Although the incidence of chronic viral hepatitis with associated complications has gradually decreased as highly effective antiviral therapies have been established, the number of patients with steatohepatitis has been increasing.This retrospective study examined data of 229 patients from 22 hospitals in our region. We examined 155 cases of chronological data and assessed the development of liver fibrosis and evaluated hepatic reserve-related markers such as platelet count, FIB-4 index, prothrombin time, and serum albumin concentration. We analyzed the relationship of these chronological changes and the incidence of NAFLD related serious complications.Data related to liver fibrosis progression, albumin, and prothrombin time were significantly associated with the occurrence of serious complications associated with cirrhosis. We compared 22 event and 133 nonevent cases of chronological changes in the data per year and found that serum albumin concentration was significantly lower in the group that developed serious complications (event cases: -0.21 g/dL/year, nonevent cases: -0.04 g/dL/year (P < .001)). This albumin decline was only the associated factor with the event incidence by multivariate analysis (P < .01).Annual decline in serum albumin concentration in patients with NAFLD is associated with serious events from the outcome of multicenter retrospective study. This highlights its potential utility as a surrogate marker to assess the efficacy of prediction of NAFLD related serious events.
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Affiliation(s)
- Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
- Department of Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Tetsuhiro Shimode
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Noriaki Orita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Masayuki Takamura
- Department of Cardiology, Kanazawa University Graduate School of Medical Sciences
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Takashi Wada
- Department of Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
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29
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Mahjoubin-Tehran M, De Vincentis A, Mikhailidis DP, Atkin SL, Mantzoros CS, Jamialahmadi T, Sahebkar A. Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis. Mol Metab 2021; 50:101049. [PMID: 32673798 PMCID: PMC8324680 DOI: 10.1016/j.molmet.2020.101049] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE The prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH) is increasing. NAFLD/NASH may progress to cirrhosis and hepatocellular carcinoma. However, most patients with NAFLD/NASH will die from a vascular cause. There are no approved pharmacological treatments for NASH/NAFLD. Many clinical trials have been, or are being, undertaken; however, the challenge is the assessment of the clinical endpoint. The main objective of this narrative review was to evaluate the efficacy of drugs used in clinical trials for the treatment of NAFLD/NASH that included a liver biopsy as the gold standard. METHODS A literature search was conducted using 3 databases (PubMed, Scopus, and Google Scholar) to identify the clinical trials that included liver biopsy assessment before and after treatment. RESULTS Interventional clinical trials (n = 33) involving 18 different agents, alone and in combination, were identified. Pioglitazone is the only agent that has shown consistent benefit and efficacy in clinical trials. Pentoxifylline, rosiglitazone, and ursodeoxycholic acid had both positive and negative results from clinical trials. There is also evidence for vitamin E and metformin. Other drugs, including bicyclol, cysteamine bitartrate, l-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins, each had a single clinical study. CONCLUSIONS In summary, the available molecules demonstrated a significant improvement in NASH and/or liver fibrosis in a minority of patients; thus, other drugs should be identified, possibly those acting on alternative pathophysiological pathways, and tested for their safety and efficacy.
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Affiliation(s)
- Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Antonio De Vincentis
- Clinical Medicine and Hepatology Unit, Campus Bio-Medico University of Rome, via Alvaro del Portillo, 200, 00128 Rome, Italy
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | | | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
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Li H, Yu XH, Ou X, Ouyang XP, Tang CK. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog Lipid Res 2021; 83:101109. [PMID: 34097928 DOI: 10.1016/j.plipres.2021.101109] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.
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Affiliation(s)
- Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China
| | - Xiang Ou
- Department of Endocrinology, the First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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Kalogirou MS, Patoulias D, Haidich AB, Akriviadis E, Sinakos E. Liraglutide in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol 2021; 45:101568. [PMID: 33309563 DOI: 10.1016/j.clinre.2020.10.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/04/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND A few randomized controlled trials (RCTs) have assessed the use of liraglutide as a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). We aimed at critically appraising and summarizing these RCTs, providing precise effect estimates regarding the safety and efficacy of liraglutide in NAFLD. METHODS We searched major databases and grey literature from their inception to May 2019, for RCTs comparing liraglutide with placebo or active comparator in patients with NAFLD. We defined as primary efficacy outcomes the observed changes in hepatic fat content (HFC) and alanine aminotransferase levels (ALT). Metabolic outcomes of interest and major safety endpoints were also assessed. RESULTS We included five trials with 371 randomised participants in total. Liraglutide produced a non-significant decrease in HFC and ALT levels, compared to control. It induced a significant reduction in body mass index, primarily driven by reduction in patients with type 2 diabetes, while it did not affect significantly glycated hemoglobin levels and Homeostatic Model Assessment of Insulin Resistance. We also showed that liraglutide significantly decreased serum triglyceride levels, also driven by the observed reduction in patients with type 2 diabetes, however it did not significantly affect the rest lipid parameters. Liraglutide was associated with increased incidence of gastrointestinal adverse events, while, no other safety issues were identified. CONCLUSION Our results do not substantiate the use of liraglutide in patients with NAFLD yet, despite its promising role.
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Affiliation(s)
- Maria-Styliani Kalogirou
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Greece
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Greece.
| | - Anna-Bettina Haidich
- Department of Hygiene, Social and Preventive Medicine and Medical Statistics, Medical School, Aristotle University of Thessaloniki, Greece
| | - Evangelos Akriviadis
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Greece
| | - Emmanouil Sinakos
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Greece
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Roskilly A, Hicks A, Taylor EJ, Jones R, Parker R, Rowe IA. Fibrosis progression rate in a systematic review of placebo-treated nonalcoholic steatohepatitis. Liver Int 2021; 41:982-995. [PMID: 33283415 DOI: 10.1111/liv.14749] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 10/06/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis is the critical determinant of liver-related outcomes in persons with nonalcoholic fatty liver disease. The rate that fibrosis develops determines the time taken to reach cirrhosis and consequent clinical outcomes. Estimates of the fibrosis progression rate (FPR) are uncertain having been defined in small observational series that rely largely on nonstandardised repeat biopsy in selected patients. The aim of this study was to evaluate the FPR in placebo-treated participants with nonalcoholic steatohepatitis (NASH) in randomised controlled trials (RCTs). METHODS Systematic review and meta-analysis of RCTs in NASH with data on fibrosis change extracted. Calculated fibrosis progression rates were pooled in meta-analysis. The pooled estimate was then used to model the proportion of hypothetical cohorts starting with no fibrosis at the age of 30 who develop cirrhosis. RESULTS A total of 35 trials including 1419 placebo-treated participants who underwent repeat liver biopsy were evaluated. Considering all trials, the overall FPR was 0.00 stages per year, increasing to 0.03 stages per year in both trials at low risk of bias and trials including >50 placebo-treated participants. This estimate was markedly lower than the value derived from previously pooled analyses of observational data. Using a FPR of 0.03 resulted in a substantial reduction in the proportion of patients developing cirrhosis compared with the FPR derived from observational studies (13% vs 28%). CONCLUSIONS The FPR in placebo-treated participants in RCTs is lower than that described from observational data. Slower fibrosis progression predicts fewer persons with NASH will progress to cirrhosis than previously estimated.
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Affiliation(s)
- Anna Roskilly
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Amy Hicks
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Richard Parker
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Ian A Rowe
- Leeds Liver Unit, St James's University Hospital, Leeds, UK.,Leeds Institute for Medical Research and Leeds Institute for Data Analytics, University of Leeds, Leeds, UK
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33
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Abou Assi R, Abdulbaqi IM, Siok Yee C. The Evaluation of Drug Delivery Nanocarrier Development and Pharmacological Briefing for Metabolic-Associated Fatty Liver Disease (MAFLD): An Update. Pharmaceuticals (Basel) 2021; 14:215. [PMID: 33806527 PMCID: PMC8001129 DOI: 10.3390/ph14030215] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/27/2021] [Indexed: 12/11/2022] Open
Abstract
Current research indicates that the next silent epidemic will be linked to chronic liver diseases, specifically non-alcoholic fatty liver disease (NAFLD), which was renamed as metabolic-associated fatty liver disease (MAFLD) in 2020. Globally, MAFLD mortality is on the rise. The etiology of MAFLD is multifactorial and still incompletely understood, but includes the accumulation of intrahepatic lipids, alterations in energy metabolism, insulin resistance, and inflammatory processes. The available MAFLD treatment, therefore, relies on improving the patient's lifestyle and multidisciplinary pharmacotherapeutic options, whereas the option of surgery is useless without managing the comorbidities of the MAFLD. Nanotechnology is an emerging approach addressing MAFLD, where nanoformulations are suggested to improve the safety and physicochemical properties of conventional drugs/herbal medicines, physical, chemical, and physiological stability, and liver-targeting properties. A wide variety of liver nanosystems were constructed and delivered to the liver, only those that addressed the MAFLD were discussed in this review in terms of the nanocarrier classes, particle size, shape, zeta potential and offered dissolution rate(s), the suitable preparation method(s), excipients (with synergistic effects), and the suitable drug/compound for loading. The advantages and challenges of each nanocarrier and the focus on potential promising perspectives in the production of MAFLD nanomedicine were also highlighted.
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Affiliation(s)
- Reem Abou Assi
- Thoughts Formulation Laboratory, Discipline of Pharmaceutical Technology, School of Pharmaceutical Sciences, University Sains Malaysia, Minden 11800, Penang, Malaysia;
- Discipline of Pharmaceutical Technology, College of Pharmacy, Al-Kitab University, Altun-Kupri, Kirkuk 36001, Iraq;
| | - Ibrahim M. Abdulbaqi
- Discipline of Pharmaceutical Technology, College of Pharmacy, Al-Kitab University, Altun-Kupri, Kirkuk 36001, Iraq;
- Pharmaceutical Design and Simulation (PhDS) Lab, Discipline of Pharmaceutical Technology, School of Pharmaceutical Sciences, University Sains Malaysia, Minden 11800, Penang, Malaysia
| | - Chan Siok Yee
- Thoughts Formulation Laboratory, Discipline of Pharmaceutical Technology, School of Pharmaceutical Sciences, University Sains Malaysia, Minden 11800, Penang, Malaysia;
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Bennett H, Troutman TD, Sakai M, Glass CK. Epigenetic Regulation of Kupffer Cell Function in Health and Disease. Front Immunol 2021; 11:609618. [PMID: 33574817 PMCID: PMC7870864 DOI: 10.3389/fimmu.2020.609618] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
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Affiliation(s)
- Hunter Bennett
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ty D Troutman
- Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Mashito Sakai
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States.,Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo, Japan
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States.,Department of Medicine, University of California, San Diego, La Jolla, CA, United States
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35
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Cho Y, Kim RH, Park H, Wang HJ, Lee H, Kang ES. Effect of Ezetimibe on Glucose Metabolism and Inflammatory Markers in Adipose Tissue. Biomedicines 2020; 8:biomedicines8110512. [PMID: 33217950 PMCID: PMC7698625 DOI: 10.3390/biomedicines8110512] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/09/2020] [Accepted: 11/16/2020] [Indexed: 01/14/2023] Open
Abstract
Despite numerous studies, the effects of ezetimibe on glucose metabolism are poorly understood. Here, we aimed to investigate the effects of ezetimibe on glucose metabolism and the expression of inflammatory markers. Thirteen rats were randomly assigned to an ezetimibe (n = 6) or control group (n = 7). The control group received a high fat diet (HFD; 60 Kcal%), whereas the ezetimibe group received an HFD (60 Kcal%) containing 160 mg/kg of ezetimibe. After 14 weeks, adipose and liver tissues, along with plasma, were collected and comparatively analyzed. The effects of combination therapy with ezetimibe and statins on glucose metabolism were investigated over a 1-year period using data from patients with hyperlipidemia. Several indices of glucose metabolism partially improved in the ezetimibe group. The sizes of adipocytes and the accumulation of pro-inflammatory cytokines were reduced in the ezetimibe group. Ezetimibe treatment induced anti-inflammatory cytokines and fatty acid oxidation in adipocytes and reduced serum levels of free fatty acids. Clinical data analysis revealed that statin monotherapy significantly increased insulin resistance. However, combination therapy with ezetimibe and statins did not increase insulin resistance. In conclusion, ezetimibe was found to reduce the sizes of adipocytes in visceral fat and serum levels of free fatty acids, to induce fatty acid oxidation, to improve adipocytic inflammation, and to partially improve glycemic index values.
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Affiliation(s)
- Yongin Cho
- Department of Endocrinology and Metabolism, Inha University School of Medicine, Incheon 22332, Korea;
- Graduate School, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Ryeong-Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (R.-H.K.); (H.J.W.)
| | - Hyunki Park
- Biobehavioral Research Center, Mo-Im Kim Nursing Research Institute, Yonsei University College of Nursing, Seoul 03722, Korea; (H.P.); (H.L.)
| | - Hye Jin Wang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (R.-H.K.); (H.J.W.)
| | - Hyangkyu Lee
- Biobehavioral Research Center, Mo-Im Kim Nursing Research Institute, Yonsei University College of Nursing, Seoul 03722, Korea; (H.P.); (H.L.)
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (R.-H.K.); (H.J.W.)
- Correspondence: ; Tel.: +82-2-2228-1968; Fax: +82-2-393-6884
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Malhotra P, Gill RK, Saksena S, Alrefai WA. Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases. Front Med (Lausanne) 2020; 7:467. [PMID: 32984364 PMCID: PMC7492531 DOI: 10.3389/fmed.2020.00467] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/13/2020] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem associated with obesity and other features of the metabolic syndrome including insulin resistance and dyslipidemia. The accumulation of lipids in hepatocytes causes liver damage and triggers inflammation, fibrosis, and cirrhosis. Beside fatty acids and triglycerides, evidence showed an increased accumulation of free cholesterol in the liver with subsequent toxic effects contributing to liver damage. The maintenance of cholesterol homeostasis in the body requires a balance between several pathways responsible for cholesterol synthesis, transport and conversion into bile acids. Intestinal absorption is also one of the major determinants of cholesterol homeostasis. The nature of changes in cholesterol homeostasis associated with NAFLD has been a subject of extensive investigations. In this article, we will attempt to provide a brief overview of the current knowledge about the disturbances in cholesterol metabolism associated with NAFLD and discuss how certain molecular targets of these pathways could be exploited for the treatment of this multifactorial disease.
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Affiliation(s)
- Pooja Malhotra
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.,Jesse Brown VA Medical Center, Chicago, IL, United States
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.,Jesse Brown VA Medical Center, Chicago, IL, United States
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Jalili R, Somi MH, Hosseinifard H, Salehnia F, Ghojazadeh M, Makhdami N, Shirmohammadi M. The Evaluation of Effective Drugs for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review and Network Meta-Analysis. Adv Pharm Bull 2020; 10:542-555. [PMID: 33072533 PMCID: PMC7539311 DOI: 10.34172/apb.2020.065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/07/2020] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis are two forms of fatty liver disease with benign and malignant nature, respectively. These two conditions can cause an increased risk of liver cirrhosis and hepatocellular carcinoma. Given the importance and high prevalence of NAFLD, it is necessary to investigate the results of different studies in related scope to provide a clarity guarantee of effectiveness. Therefore, this systematic review and meta-analysis aim to study the efficacy of various medications used in the treatment of NAFLD. Methods: A systematic search of medical databases identified 1963 articles. After exclusion of duplicated articles and those which did not meet our inclusion criteria, eta-analysis was performed on 84 articles. Serum levels of alanine aminotransferase (ALT), aspartate amino transferase (AST) were set as primary outcomes and body mass index (BMI), hepatic steatosis, and NAFLD activity score (NAS) were determined as secondary outcomes. Results: Based on the P-score of the therapeutic effects on the non-alcoholic steatohepatitis (NASH), we observed the highest efficacy for atorvastatin, tryptophan, orlistat, omega-3 and obeticholic acid for reduction of ALT, AST, BMI, steatosis and NAS respectively. Conclusion: This meta-analysis showed that atorvastatin. life-style modification, weight loss, and BMI reduction had a remarkable effect on NAFLD-patients by decreasing aminotransferases.
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Affiliation(s)
- Ramin Jalili
- Department of Internal Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Hosseinifard
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Salehnia
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Masoud Shirmohammadi
- Department of Gastroenterology, Liver, and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Glass O, Filozof C, Noureddin M, Berner-Hansen M, Schabel E, Omokaro SO, Schattenberg JM, Barradas K, Miller V, Francque S, Abdelmalek MF. Standardisation of diet and exercise in clinical trials of NAFLD-NASH: Recommendations from the Liver Forum. J Hepatol 2020; 73:680-693. [PMID: 32353483 DOI: 10.1016/j.jhep.2020.04.030] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 03/29/2020] [Accepted: 04/20/2020] [Indexed: 12/24/2022]
Abstract
Lifestyle modification is the foundation of treatment recommendations for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The design of clinical trials in NASH may be impeded by the lack of a systematic approach to identify and evaluate how lifestyle changes and/or modifications influence clinical trial outcomes and associated endpoints. Furthermore, there are additional uncertainties regarding the methods that can be utilised to better characterise and quantify lifestyle variables - which can influence disease activity and alter trial endpoints - to allow for comparisons of trial outcomes across different phases of research and/or within drug-classes. This summary by the Liver Forum's Standard of Care Working Group reviews currently available clinical data, identifies the barriers and challenges associated with the standard of care in NAFLD/NASH clinical trials, defines available assessments of lifestyle changes, and proposes approaches to better understand and define the influence of diet and exercise on NASH treatment in the context of different pharmacologic interventions. The ultimate objective is to propose tangible solutions which enable investigators, sponsors, and regulatory authorities to meaningfully interpret clinical trial outcomes and the impact of lifestyle modification on such outcomes as they pertain to phase I-IV clinical trials.
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Affiliation(s)
- Oliver Glass
- Division of General Internal Medicine, Duke University, Durham, North Carolina
| | | | - Mazen Noureddin
- Division of Digestive and Liver Diseases Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark Berner-Hansen
- Digestive Disease Center, Bispebjerg University Hospital of Copenhagen, Denmark
| | - Elmer Schabel
- Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
| | - Stephanie O Omokaro
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Jörn M Schattenberg
- Metabolic Liver Research Center, Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Katherine Barradas
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C
| | - Sven Francque
- Division of Gastroenterology & Hepatology, Antwerp University & University Hospital, Antwerp, Belgium.
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina.
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Martínez Soriano B, Güemes A, Pola G, Gonzalo A, Palacios Gasós P, Navarro AC, Martínez-Beamonte R, Osada J, García JJ. Effect of Melatonin as an Antioxidant Drug to Reverse Hepatic Steatosis: Experimental Model. Can J Gastroenterol Hepatol 2020; 2020:7315253. [PMID: 32566547 PMCID: PMC7293725 DOI: 10.1155/2020/7315253] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/25/2019] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction The hepatic steatosis of the nonalcoholic origin or NAFLD is increasing at present, particularly in Western countries, parallel to the increase in obesity, constituting one of the most prevalent hepatic processes in the Western society. Melatonin has been successfully tested in experimental models in mice as a drug capable of reversing steatosis. The effect of melatonin on fat metabolism can be summarized as a decrease in lipid peroxidation and a decrease in oxidative stress, biochemical phenomena intimately related to fat deposition in the hepatocyte. There are hardly any studies in large animals. Objective In this study, we investigate the effects of melatonin administered orally at a dose of 10 mg/kg/day to reverse established hepatic steatosis induced by a special diet in a porcine animal model. Materials and Methods We analyze the parameters of oxidative stress: malondialdehyde (MDA), 4-hydroxyalkenals (4-HDA), and carbonyls, degree of fat infiltration (analyzed by direct vision by a pathologist and by means of a computer program of image treatment), and serological parameters of lipid metabolism and hepatic damage. These parameters were analyzed in animals to which hepatic steatosis was induced by means of dietary modifications. Results We have not been able to demonstrate globally a beneficial effect of melatonin in the improvement or reversal of liver steatosis once established, induced by diet in a porcine animal model. However, we have found several signs of improvement at the histological level, at the level of lipid metabolism, and at the level of oxidative stress parameters. We have verified in our study that, in the histological analysis of the liver sample by means of the program image treatment (free of subjectivity) of the animals that continue with the diet, those that consume melatonin do not increase steatosis as much as those that do not consume it significantly (p=0.002). Regarding the parameters of oxidative stress, MDA modifies in a significant manner within the group of animals that continue with the diet and take melatonin (p=0.004). As for lipid metabolism, animals that maintain the steatotic diet and take melatonin lower total and LDL cholesterol levels and increase HDL levels, although these results do not acquire statistical significance. Conclusions In this study, it has not been possible to demonstrate a beneficial effect of melatonin in the improvement or reversal of liver steatosis once established and induced by diet in the porcine model. It is true that signs of improvement have been found at the histological level, at the level of lipid metabolism, and at the level of oxidative stress phenomena, when comparing animals with established steatosis that are treated with melatonin with those who do not take it. This work is the first study conducted in a large animal model in which the effect of melatonin is studied as a treatment in the reversal of established hepatic steatosis.
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Affiliation(s)
| | - Antonio Güemes
- Department of Surgery, University Hospital Lozano Blesa, Zaragoza, Spain
| | - Guillermo Pola
- Department of Surgery, General Defense Hospital, Zaragoza, Spain
| | - Azucena Gonzalo
- Department of Surgery, University Hospital Lozano Blesa, Zaragoza, Spain
| | | | - Ana C. Navarro
- Department of Surgery, University Hospital Lozano Blesa, Zaragoza, Spain
| | | | - Jesús Osada
- Department of Biochemistry and Molecular and Cellular Biology, University of Zaragoza, Zaragoza, Spain
| | - José J. García
- Department of Physiology, University of Zaragoza, Zaragoza, Spain
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Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, Iida N, Arai K, Yamashita T, Harada K, Gabata T, Nakamura H, Kaneko S, Takamura T. Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Diabetes Ther 2020; 11:549-560. [PMID: 31956961 PMCID: PMC6995806 DOI: 10.1007/s13300-020-00762-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to reduction in liver fibrosis scores during the course of nonalcoholic fatty liver disease (NAFLD) development. We will test our hypothesis that lowering glucose and increasing insulin reduce liver fibrosis in NAFLD. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels and sulfonylureas increase insulin levels, while both lower glucose levels. METHODS This study is a 48-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The sample size was calculated to be 14 in each group with a significance level of 0.05 and power of 0.90. The design required 40 evaluable patients in this study. The primary endpoint of this study will be the improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. The secondary efficacy endpoints in the present study include organ-specific insulin sensitivity, insulin/glucagon secretion, ectopic fat accumulation, bioelectrical impedance analysis, sympathetic nerve activity, comprehensive gene expression analyses in the liver and blood cells, and gut microbiota profiling. PLANNED OUTCOMES Recruitment into this study started in November 2015 and will end in September 2020, with 40 patients randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by the end of 2022. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000020544) and ClinicalTrials.gov (NCT02649465).
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takehiro Kanamori
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuka Kaikoi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noboru Takata
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
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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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Iqbal Z, Dhage S, Mohamad JB, Abdel-Razik A, Donn R, Malik R, Ho JH, Liu Y, Adam S, Isa B, Stefanutti C, Soran H. Efficacy and safety of PCSK9 monoclonal antibodies. Expert Opin Drug Saf 2019; 18:1191-1201. [DOI: 10.1080/14740338.2019.1681395] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Zohaib Iqbal
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Shaishav Dhage
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | | | - Alaa Abdel-Razik
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Rachelle Donn
- Cardiovascular Research Group, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Rayaz Malik
- Department of Medicine, Weill Cornell Medical College, Doha, Qatar
| | - Jan Hoong Ho
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Yifen Liu
- Cardiovascular Research Group, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Safwaan Adam
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Basil Isa
- Department of Endocrinology and Diabetes, Wythenshawe Hospital, Manchester, UK
| | - Claudia Stefanutti
- Department of Molecular Medicine, Sapienza’ University of Rome, Rome, Italy
| | - Handrean Soran
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
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Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17:616-629.e26. [PMID: 29913275 DOI: 10.1016/j.cgh.2018.06.011] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 06/06/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018. RESULTS We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the nonalcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with a small amount of heterogeneity (I2 = 27%). There were improvements by at least 1 point in steatosis scores of 33% ± 3% of patients, in hepatocyte ballooning scores of 30% ± 3% of patients, in lobular inflammation scores of 32% ± 3% of patients, and in fibrosis scores of 21% ± 3% of patients, with a moderate amount of heterogeneity among trials (I2 range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72 ± 0.19), with a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45% ± 0.54%) with moderate heterogeneity (I2 = 40%), and in magnetic resonance proton density fat fraction (by 2.43 ± 0.89), without heterogeneity (I2 = 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7 ± 3.8 U/L and 5.9 ± 2.1 U/L, respectively; P < .01 for both). CONCLUSIONS In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.
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Jun BG, Cheon GJ. The utility of ezetimibe therapy in nonalcoholic fatty liver disease. Korean J Intern Med 2019; 34:284-285. [PMID: 30840809 PMCID: PMC6406096 DOI: 10.3904/kjim.2019.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 02/18/2019] [Indexed: 01/28/2023] Open
Affiliation(s)
- Baek Gyu Jun
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
- Correspondence to Gab Jin Cheon, M.D. Division of Gastroenterology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, 38 Bangdong-gil, Gangneung 25440, Korea Tel: +82-33-610-3100 Fax: +82-33-644-5495 E-mail:
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Lee HY, Jun DW, Kim HJ, Oh H, Saeed WK, Ahn H, Cheung RC, Nguyen MH. Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis. Korean J Intern Med 2019; 34:296-304. [PMID: 29551054 PMCID: PMC6406097 DOI: 10.3904/kjim.2017.194] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 07/14/2017] [Accepted: 08/01/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS A number of clinical trials reported varying effects of cholesterol lowering agents in nonalcoholic fatty liver disease (NAFLD) patients. We, therefore, assessed the changes in hepatic steatosis and NAFLD activity score (NAS) after treatment with cholesterol lowering agents in NAFLD patients by metaanalysis. METHODS The Cochrane Library, the MEDLINE, and the Embase databases were searched until May 2015, without any language restrictions, for randomized controlled trials (RCTs) and nonrandomized studies (NRSs). Additional references were obtained from review of bibliography of relevant articles. The quality of evidence was assessed using the grading of recommendations assessment, development and evaluation guidelines. RESULTS Three RCTs (n = 98) and two NRSs (n = 101) met our study inclusion criteria (adult, NAFLD, liver biopsy). Liver biopsy was performed in all five studies, but only the three studies reported NAS. Ezetimibe significantly decreased NAS (standardized mean difference [SMD], -0.30; 95% confidence interval [CI], -0.57 to -0.03) but not hepatic steatosis in RCT (SMD, -0.1; 95% CI, -0.53 to 0.32), while the effect was significant for both NAS and intrahepatic content in NRSs (SMD, -3.0; 95% CI, -6.9 to 0.91). CONCLUSION Ezetimibe decreased NAS without improving hepatic steatosis.
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Affiliation(s)
- Hyo Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyunwoo Oh
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Waqar Khalid Saeed
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Hyeongsik Ahn
- Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ramsey C. Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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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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Speliotes EK, Balakrishnan M, Friedman LS, Corey KE. Treatment of Dyslipidemia in Common Liver Diseases. Clin Gastroenterol Hepatol 2018; 16:1189-1196. [PMID: 29684459 PMCID: PMC6558967 DOI: 10.1016/j.cgh.2018.04.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 03/22/2018] [Accepted: 04/13/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Elizabeth K. Speliotes
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Maya Balakrishnan
- Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine, Houston, Texas
| | - Lawrence S. Friedman
- Departments of Medicine, Harvard Medical School, Tufts University School of Medicine, Newton-Wellesley Hospital, and Massachusetts General Hospital, Boston, Massachusetts
| | - Kathleen E. Corey
- Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Simon TG, Corey KE, Cannon CP, Blazing M, Park JG, O'Donoghue ML, Chung RT, Giugliano RP. The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int J Cardiol 2018; 270:245-252. [PMID: 29903515 DOI: 10.1016/j.ijcard.2018.05.087] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/15/2018] [Accepted: 05/22/2018] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The nonalcoholic fatty liver disease fibrosis score (NFS) is comprised of unique metabolic risk indicators that may accurately predict residual cardiovascular (CV) risk in patients with established coronary disease and metabolic dysfunction. METHODS We applied the NFS prospectively to 14,819 post-ACS patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), in the IMPROVE-IT trial, using validated NFS cutoffs. The primary endpoint included CV death, myocardial infarction, unstable angina, revascularization or stroke. Outcomes were compared between NFS categories and treatment arms using frequency of events, KM rates and adjusted Cox proportional hazard models. The ability of the NFS to predict recurrent CV events was independently validated in 5395 placebo-treated patients enrolled in the SOLID-TIMI 52 trial. RESULTS Among 14,819 patients enrolled in IMPROVE-IT, 14.2% (N = 2106) were high-risk (NFS > 0.67). The high-risk group had a 30% increased risk of recurrent major CV events, compared to the low-risk NFS group (HR 1.30 [1.19-1.43]; p < 0.001). Among high-risk patients, ezetimibe/simvastatin conferred a 3.7% absolute reduction in risk of recurrent CV events, compared to placebo/simvastatin (HR 0.85 [0.74-0.98]), translating to a number-needed-to-treat of 27. Similar benefit was not found in the low-risk group (HR ezetimibe/simvastatin vs. placebo/simvastatin, 1.01 [0.91-1.12]; p-interaction = 0.053). The relationship between NFS category and recurrent CV events was independently validated in patients enrolled in SOLID-TIMI 52 (HR for NFS > 0.67 vs. NFS < -1.455 = 1.55 [1.32-1.81]; p < 0.001). CONCLUSION Stratification of cardiovascular risk by NFS identifies an independent population of patients who are at highest risk of recurrent events, and most likely to benefit from dual lipid-lowering therapy. Clinical trials.gov: NCT00202878.
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Affiliation(s)
- Tracey G Simon
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, United States; Harvard Medical School, Boston, MA, United States
| | - Kathleen E Corey
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, United States; Harvard Medical School, Boston, MA, United States
| | - Christopher P Cannon
- Harvard Medical School, Boston, MA, United States; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, United States
| | | | - Jeong-Gun Park
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, United States
| | - Michelle L O'Donoghue
- Harvard Medical School, Boston, MA, United States; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, United States
| | - Raymond T Chung
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, United States; Harvard Medical School, Boston, MA, United States
| | - Robert P Giugliano
- Harvard Medical School, Boston, MA, United States; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, United States.
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Wu H, Shang H, Wu J. Effect of ezetimibe on glycemic control: a systematic review and meta-analysis of randomized controlled trials. Endocrine 2018; 60:229-239. [PMID: 29397561 DOI: 10.1007/s12020-018-1541-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/17/2018] [Indexed: 12/27/2022]
Abstract
PURPOSE Given the increased risk of incident diabetes and the side effects on glycemic control with statin treatment, statin and ezetimibe combination therapy has been widely used. However, whether the same concern exists in ezetimibe remains uncertain. This meta-analysis aimed to investigate the influence of ezetimibe treatment on glycemic control. METHODS Articles were searched from PubMed, EMBASE, and Cochrane Library. Randomized controlled trials (RCTs) were included if they compared the effects of ezetimibe with placebo, ezetimibe plus statin with the same statin, or low-dose stain plus ezetimibe with high-dose statin on FBG and glycosylated hemoglobin A1c (HbA1c). RESULTS Of the 2440 articles retrieved, 16 RCTs were included. Ezetimibe did not cause side effects on FBG (WMD -0.62, 95% CI: -3.13 to 1.90) and HbA1c (WMD 0.07, 95% CI: -0.07 to 0.20%). No significant changes in FBG (WMD -1.78, 95% CI: -6.33 to 2.77%) and HbA1c (WMD -0.05, 95% CI: -0.14 to 0.05%) were observed in ezetimibe plus low-dose statin treatment compared with high-dose statin. According to subgroup analysis, in comparison with high-dose statin, ezetimibe plus low-dose statin taken for more than 3 months showed a significant decrease in FBG (WMD -7.12, 95% CI: -13.86 to -0.38%) compared with that taken for less than 3 months (WMD 0.90, 95% CI: -2.91 to 4.71%). Nevertheless, this difference was invalid when the study conducted by Dagli et al. was removed. CONCLUSIONS Compared with high-dose statin therapy, ezetimibe with low-dose statin for more than 3 months may have a beneficial tendency of effects on glycemic control.
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Affiliation(s)
- Huijin Wu
- The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157009, China.
| | - Hua Shang
- The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157009, China
| | - Jing Wu
- The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157009, China
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Imprialos KP, Stavropoulos K, Doumas M, Skalkou A, Zografou I, Athyros VG. The potential role of statins in treating liver disease. Expert Rev Gastroenterol Hepatol 2018; 12:331-339. [PMID: 29431526 DOI: 10.1080/17474124.2018.1439379] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins are commonly use for the management of dyslipidemia, worldwide. Various studies have demonstrated that statins offer significant reduction in the risk of cardiovascular morbidity and mortality. However, this class of drugs has been implicated in potential liver toxicity, thus has been considered as a 'forbidden-drug' in patients with increased liver enzymes. Areas covered: Studies have shown that statins might offer clinical benefits in the setting of viral hepatitis, progression of cirrhosis, and hepatocellular carcinoma. More importantly, this class of drugs was shown to ameliorate liver histological (in both imaging and biopsy studies) and functional alterations in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In addition, two large survival studies have demonstrated reduction in the risk for cardiovascular events with statin use in patients with elevated transaminase levels at baseline. Expert commentary: These benefits were of greater extent compared with patients with normal liver function tests at baseline. However, current international guidelines seem to neglect these findings and are not including statins in the management algorithm of patients with non-alcoholic fatty liver disease or steatohepatitis. Future randomized studies providing biopsy-proven benefits will establish the use of statins in the prevention of cardiovascular events and therapeutic algorithm of these patients.
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Affiliation(s)
- Konstantinos P Imprialos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Konstantinos Stavropoulos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Michael Doumas
- b Veterans Affairs Medical Center , George Washington University , Washington , DC , USA
| | - Anastasia Skalkou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Ioanna Zografou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Vasilios G Athyros
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
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