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Yang X, Chen Q, Zhang Q, Yu Z. Lipoprotein cholesterol ratios and cardiovascular disease risk in US adults: a cross-sectional study. Front Nutr 2025; 12:1529223. [PMID: 40313882 PMCID: PMC12043482 DOI: 10.3389/fnut.2025.1529223] [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: 11/16/2024] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Background The ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) has been introduced as a novel indicator to evaluate lipid metabolism. The study explored the association between NHHR and cardiovascular disease (CVD). Methods A cross-sectional study was achieved by utilizing data obtained from the NHANES (2003-2016). The association between NHHR and CVD was assessed by multivariate logistic regression analysis (LRA) and the restricted cubic spline (RCS) analysis. Also, interaction tests and subgroup analyses were employed to explore whether the associations differ by subgroups. Then, threshold analysis were conducted for interval delineation and detection of threshold effects with two-segment piecewise LR model. Results A cohort of 11,471 individuals was involved. The results indicated that the linear relationship between NHHR and CVD was not significant (P for trend >0.05). The RCS analysis revealed a non-linear J-shaped association of NHHR with CVD risk. A two-segment LR model was established to assess the threshold effect of the NHHR. A log-likelihood ratio test (P < 0.001) suggested that the two-segment LR model exhibited better performances compared with the single-line LR model. Additionally, a tangent point of the NHHR occurred at 2.82, and the likelihood of CVD increased by 21% as the NHHR increased by one unit (OR = 1.21, 95% CI = 1.10-1.34). Conclusions A J-shaped association was detected between NHHR and the prevalence of CVD, suggesting that NHHR could serve as a novel assessment marker for identifying high-risk CVD populations. However, further cohort studies are needed to confirm this finding.
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Affiliation(s)
- Xiuming Yang
- Department of Cardiology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Qiuyun Chen
- Department of Cardiology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Qingyu Zhang
- Department of Cardiology, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Kunshan, Jiangsu, China
| | - Zongliang Yu
- Department of Cardiology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
- Department of Cardiology, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Kunshan, Jiangsu, China
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Ha YS, Kim W, Kim SJ. Unraveling the role of GOLM1-OPN-ABCG5 axis in MASH: Editorial on "GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers". Clin Mol Hepatol 2025; 31:628-630. [PMID: 39815769 PMCID: PMC12016591 DOI: 10.3350/cmh.2025.0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 01/18/2025] Open
Affiliation(s)
- Yoon-su Ha
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Korea
- Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon, Korea
| | - Won Kim
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Seoul National University College of Medicine Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Seung-Jin Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Korea
- Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon, Korea
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3
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Barua L, Akhter T, Bhuiyan R, Sathi HA, Banik PC, Faruque M, Rahman MA, Islam SMS. Association of Cardiovascular Disease Risk Factors With Estimated Dietary Salt Consumption in Bangladeshi Adults: A Nationally Representative Cross-Sectional Study. J Clin Hypertens (Greenwich) 2025; 27:e14966. [PMID: 39822059 PMCID: PMC11771797 DOI: 10.1111/jch.14966] [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] [Indexed: 01/19/2025]
Abstract
This population-based, nationally representative cross-sectional study assessed the daily salt consumption status and its associated cardiovascular disease (CVD) risk factors using weighted data from the STEPwise approach to noncommunicable disease risk factor surveillance conducted in 2018 in Bangladesh. It included a non-institutionalized adults' population of 6189 men and women aged 18-69 years. Their daily salt consumption was estimated using the spot urine sodium concentration following the Tanaka equation and reported according to the standard nomenclature proposed by the World Hypertension League and partner organizations involved in dietary salt reduction. Out of a total of 6189 participants, 2.4% consumed the recommended amount of salt (<5 g/day), 67.8% consumed a high amount of salt (≥5-10 g/day), 27.2% consumed a very high amount of salt (>10-15 g/day), and 2.6% consumed an extremely high amount of salt (>15 g/day). In univariate analysis, a higher than recommended level of salt intake (≥5 g/day) was significantly prevalent among rural residents (high = 78.4%, very-high = 81.6%, extremely-high = 84.9%, p = 0.01), literates (high = 51.6%, very-high = 57.9%, extremely-high = 59.1%, p = 0.02), newly diagnosed hypertension (high = 20.6%, very-high = 23.6%, extremely-high = 24.1%, p = 0.008), and overweight/obese (high = 25.9%, very-high = 33.3%, extremely-high = 29.8%, p = 0.000). Similarly, in ordinal logistic regression analysis, the categories of daily salt consumption showed a significant association with rural residence (OR: 1.300, CI: 1.109-1.524, p = 0.001), literates (OR: 0.777, CI: 0.671-0.900, p = 0.001), newly diagnosed hypertension (OR: 1.204, CI: 1.022-1.419, p = 0.026), and overweight/obesity (OR: 1.353, CI: 1.145-1.598, p = 0.000). The current national pattern of salt consumption in Bangladesh may help reconstruct the salt reduction strategy considering the associated risk factors.
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Affiliation(s)
- Lingkan Barua
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Tahmina Akhter
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Rijwan Bhuiyan
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Halima Akter Sathi
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Palash Chandra Banik
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Mithila Faruque
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
| | - Muhammad Aziz Rahman
- Department of Noncommunicable DiseasesBangladesh University of Health Sciences (BUHS)DhakaBangladesh
- Institute of Health and WellbeingFederation University AustraliaBerwickVICAustralia
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Wan W, Wei R, Xu B, Cao H, Zhi Y, Guo F, Liu H, Li B, Wu J, Gao Y, Zhang K. Qiwei Jinggan Ling regulates oxidative stress and lipid metabolism in alcoholic liver disease by activating AMPK. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156125. [PMID: 39388920 DOI: 10.1016/j.phymed.2024.156125] [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: 05/08/2024] [Revised: 06/24/2024] [Accepted: 07/09/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is a severe public health concern worldwide and there is still a lack of effective treatments. Qiwei Jinggan Ling (QJL) has protective effects against various liver injuries, but its pharmacological action on ALD has received little attention. PURPOSE To investigate the effect and mechanism of QJL on ALD in vivo and in vitro. METHODS In vivo, an ALD mouse model was established by alcohol combined with a high-fat diet (HFD) and treated with QJL. Biochemical indicators, HE staining, and Oil Red O staining were employed to assess hepatic oxidative stress, steatosis, and alcohol metabolism. RNA sequencing analysis was performed, and the results were verified by qRT-PCR and Western blot to elucidate the hepatoprotective mechanism of QJL. In vitro, HepG2 cells were co-stimulated with NaOA (sodium oleate) and EtOH (ethanol), followed by intervention with Compound C (CC, AMPK inhibitor) and QJL-containing serum. Oil Red O, BODIPY (boron-dipyrromethene), and ROS (reactive oxygen species) staining were applied to validate the efficacy and mechanism of QJL-containing serum. The expression of AMP-activated protein kinase (AMPK) pathway-related factors was analyzed through qRT-PCR and Western blot for additional corroboration. Moreover, the key pharmacodynamic components of QJL were identified by UPLC-MS/MS and molecular docking. RESULTS In vivo, QJL ameliorated liver structural disorders, steatosis, oxidative stress, and impaired alcohol metabolism, as indicated by biochemical indicators and histopathological assays. RNA sequencing analysis revealed that QJL reversed the expression of genes related to alcohol metabolism, fatty acid metabolism, and cholesterol metabolism. The results of qRT-PCR and Western blot were in line with those of RNA sequencing. Furthermore, it was discovered that QJL significantly upregulated the expression of p-AMPK and downregulated the expression of sterol regulatory element binding transcription factor 1 (SREBP-1c). In vitro, biochemical indicators and staining assays demonstrated that QJL-containing serum inhibited lipid accumulation and oxidative stress. The qRT-PCR and Western blot analysis revealed that QJL-containing serum markedly enhanced the expression of p-AMPK and carnitine palmitoyltransferase 1a (Cpt1a), while suppressing the expression of SREBP-1c, fatty acid synthase (Fasn), and acetyl-coenzyme A carboxylase 1 (ACC-1). However, CC inhibited the above pharmacological activities of QJL-containing serum. Additionally, (2S)-Liquiritigenin, Glycyrrhetinate, Isovitexin, Taxifolin, and Yohimbine were proved to be the key active components of QJL. CONCLUSION QJL had the potential to be a therapeutic drug for ALD by activating the AMPK pathway, thereby regulating lipid metabolism and inhibiting oxidative stress.
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Affiliation(s)
- Weimin Wan
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Riming Wei
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Baoling Xu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China; Department of Emergency, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, Guangxi, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Yueping Zhi
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Fengyue Guo
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Haiping Liu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Bo Li
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Jianzhao Wu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China.
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Cheng Y, Ye J, Huang J, Wang Y. The non-HDL-C to APOB ratio as a predictor of inaccurate LDL-C measurement in patients with chronic intrahepatic cholestasis and jaundice: a retrospective study. PeerJ 2024; 12:e18224. [PMID: 39376224 PMCID: PMC11457871 DOI: 10.7717/peerj.18224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 09/12/2024] [Indexed: 10/09/2024] Open
Abstract
Background Cholestasis is characterized by the accumulation of bile in the liver or biliary system due to obstruction or impaired flow, necessitating lipid profiling to assess lipid metabolism abnormalities. Intrahepatic cholestasis, being the most significant type of cholestasis, further complicates the assessment of lipid abnormalities. However, the accuracy of low-density lipoprotein cholesterol (LDL-C) measurement in intrahepatic cholestasis patients remains uncertain. Objective This study aimed to evaluate the consistency of the homogeneous assay and the Friedewald formula in detecting LDL-C levels and identify factors influencing LDL-C test results in intrahepatic patients with cholestasis. Methods Retrospective analysis of laboratory data was conducted on intrahepatic cholestatic patients. Correlations between LDL-C values obtained using the homogeneous method (LDL-C(D)) and the Friedewald formula (LDL-C(F)), as well as associations between high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1), LDL-C(D) and LDL-C(F), and apolipoprotein B (ApoB), were analyzed. Logistic regression analyses were employed to identify diagnostic indicators for inaccurate LDL-C measurements in intrahepatic cholestatic patients. Results Compared to patients with intrahepatic cholestasis without jaundice, the correlation between LDL-C(F) and LDL-C(D) was weaker in those with jaundice. Additionally, HDL-C exhibited a strong correlation with ApoA1 in both jaundice and non-jaundice cholestasis cases. Elevated non-HDL-C to APOB ratio (NH-C/B Ratio) levels (>4.5) were identified as a reliable predictor of inaccurate LDL-C measurements in patients with chronic intrahepatic cholestasis accompanied by jaundice. Conclusions LDL-C measurement reliability is moderately weaker in patients with intrahepatic cholestasis accompanied by jaundice. Elevated levels of the NH-C/B ratio serve as a significant predictor of inaccurate LDL-C measurements in this chronic patient population, highlighting its clinical relevance for diagnostic assessments.
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Affiliation(s)
- Yongjiang Cheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Canton, Guangdong Province, China
| | - Jingyan Ye
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Canton, Guangdong Province, China
| | - Junyuan Huang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Canton, Guangdong Province, China
| | - Yang Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Canton, Guangdong Province, China
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Qiang E, Xu H. PGE 2 synthesis and signaling in the liver physiology and pathophysiology: An update. Prostaglandins Other Lipid Mediat 2024; 174:106875. [PMID: 39019102 DOI: 10.1016/j.prostaglandins.2024.106875] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/12/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024]
Abstract
The liver plays a central role in systemic metabolism and drug degradation. However, it is highly susceptible to damage due to various factors, including metabolic imbalances, excessive alcohol consumption, viral infections, and drug influences. These factors often result in conditions such as fatty liver, hepatitis, and acute or chronic liver injury. Failure to address these injuries could promptly lead to the development of liver cirrhosis and potentially hepatocellular carcinoma (HCC). Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid that belongs to the class of polyunsaturated fatty acids (PUFA) and is synthesized via the cyclooxygenase (COX) pathway. By binding to its G protein coupled receptors (i.e., EP1, EP2, EP3 and EP4), PGE2 has a wide range of physiological and pathophysiology effects, including pain, inflammation, fever, cardiovascular homeostasis, etc. Recently, emerging studies showed that PGE2 plays an indispensable role in liver health and disease. This review focus on the research progress of the role of PGE2 synthase and its receptors in liver physiological and pathophysiological processes and discuss the possibility of developing liver protective drugs targeting the COXs/PGESs/PGE2/EPs axis.
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Affiliation(s)
- Erjiao Qiang
- Department of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Hu Xu
- Health Science Center, East China Normal University, Shanghai 200241, China.
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Saijou E, Kamiya Y, Fujiki K, Shirahige K, Nakato R. Modulation of liver cholesterol homeostasis by choline supplementation during fibrosis resolution. Heliyon 2024; 10:e36727. [PMID: 39296030 PMCID: PMC11407984 DOI: 10.1016/j.heliyon.2024.e36727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 09/21/2024] Open
Abstract
Liver fibrosis is a critical global health challenge, often leading to severe liver diseases without timely intervention. Choline deficiency has been linked to metabolic dysfunction associated steatohepatitis (MASH) and liver fibrosis, suggesting choline supplementation as a potential therapeutic approach. This study aimed to explore the therapeutic potential of choline supplementation in liver fibrosis resolution and its effects on cholesterol homeostasis using a mouse model with induced liver fibrosis. Our findings reveal that choline supplementation significantly decreases blood lactate dehydrogenase (LDH) and non-high-density lipoprotein cholesterol (non-HDL-C) levels. Transcriptome analysis showed that choline supplementation primarily induces genes related to cholesterol homeostasis, suggesting a significant impact on liver cholesterol synthesis. However, choline supplementation did not significantly alter the expression of fibrosis-related, choline metabolism-related, or epigenetics-related genes. This study provides novel insights into the role of choline in liver health and cholesterol metabolism, potentially informing treatments for liver fibrosis and related conditions.
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Affiliation(s)
- Eiko Saijou
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Yoshiko Kamiya
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Katsunori Fujiki
- Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Katsuhiko Shirahige
- Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Ryuichiro Nakato
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
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Dhakkal R, Menon J, Shanmugam N, Mishra A, Vij M, Rammohan A, Rela M. Liver transplantation for co-existing biliary atresia and familial hypercholesterolemia. Indian J Gastroenterol 2024; 43:851-853. [PMID: 37466883 DOI: 10.1007/s12664-023-01411-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Affiliation(s)
- Rabi Dhakkal
- Department of Pediatric Gastroenterology and Hepatology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India
| | - Jagadeesh Menon
- Department of Pediatric Gastroenterology and Hepatology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India.
| | - Naresh Shanmugam
- Department of Pediatric Gastroenterology and Hepatology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India
| | - Adrija Mishra
- Department of Genetics, Bione, Brigade IRV Center, Nallurhalli, Bengaluru, 560 066, India
| | - Mukul Vij
- Department of Histopathology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India
| | - Ashwin Rammohan
- Department of Hepatobiliary Surgery and Liver Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India
| | - Mohamed Rela
- Department of Hepatobiliary Surgery and Liver Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, 600 044, India
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Greco S, Campigotto M, D’Amuri A, Fabbri N, Passaro A. Dyslipidemia, Cholangitis and Fatty Liver Disease: The Close Underexplored Relationship: A Narrative Review. J Clin Med 2024; 13:2714. [PMID: 38731243 PMCID: PMC11084647 DOI: 10.3390/jcm13092714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 04/25/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
In assessing individual cardiovascular risk, dyslipidemia is known for emerging as a pivotal factor significantly contributing to major cardiovascular events. However, dyslipidemic patients frequently present with concurrent medical conditions, each with varying frequencies of occurrence; cholangitis, whether acute or chronic, and hepatic steatosis, along with associated conditions, are strongly associated with specific forms of dyslipidemia, and these associations are reasonably well elucidated. Conversely, evidence linking biliary disease to hepatic steatosis is comparatively scant. This narrative review aims to bridge this gap in knowledge concerning the interplay between dyslipidemia, cholangitis, and hepatic steatosis. By addressing this gap, clinicians can better identify patients at heightened risk of future major cardiovascular events, facilitating more targeted interventions and management strategies. The review delves into the intricate relationships between dyslipidemia and these hepatic and biliary clinical conditions, shedding light on potential mechanisms underlying their associations. Understanding these complex interactions is crucial for optimizing cardiovascular risk assessment as well and devising tailored treatment approaches for patients with dyslipidemia and associated hepatic disorders. Moreover, elucidating these connections empowers clinicians with the knowledge needed to navigate the multifaceted landscape of cardiovascular risk assessment and management effectively. By exploring the intricate relationships between dyslipidemia, cholangitis, and hepatic steatosis (without forgetting the possible clinical consequences of hepatic steatosis itself), this review not only contributes to the existing body of knowledge but also offers insights into potential avenues for further research and clinical practice. Thus, it serves as a valuable resource for healthcare professionals striving to enhance patient care and outcomes in the context of cardiovascular disease and associated hepatic conditions.
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Affiliation(s)
- Salvatore Greco
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
- Department of Internal Medicine, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy
| | - Michele Campigotto
- Gastroenterology and Digestive Endoscopy Unit, ASUGI, Cattinara University Hospital, Strada di Fiume 447, 34149 Trieste, TS, Italy;
| | - Andrea D’Amuri
- General Medicine Unit, Medical Department, ASST Mantova, Ospedale Carlo Poma, Strada Lago Paiolo 10, 46100 Mantova, MN, Italy;
| | - Nicolò Fabbri
- Department of General Surgery, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy;
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
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Park YT, Chung EY, Chae CH, Lee YH. Association between serum perfluoroalkyl substances concentrations and non-alcoholic fatty liver disease among Korean adults: a cross-sectional study using the National Environmental Health Survey cycle 4. Ann Occup Environ Med 2024; 36:e10. [PMID: 38872635 PMCID: PMC11168940 DOI: 10.35371/aoem.2024.36.e10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/20/2024] [Accepted: 03/28/2024] [Indexed: 06/15/2024] Open
Abstract
Background Perfluoroalkyl substances (PFAS) are widely used in industry and daily life due to their useful properties. They have a long half-life, accumulate in the body, and there is evidence that they are associated with biomarkers of lipid metabolism and liver damage. This may suggest non-alcoholic fatty liver disease (NAFLD) caused by PFAS. However, since there has been no study analyzing the relationship between PFAS and NAFLD in the entire population in Korea. We sought to confirm the relationship between serum PFAS concentration and NAFLD prevalence in Korean adults using the Korean National Environmental Health Survey (KoNEHS) cycle 4. Methods The study was conducted on 2,529 subjects in 2018-2019 among KoNEHS participants. For the diagnosis of NAFLD, the hepatic steatosis index (HSI) was used, and the geometric mean and concentration distribution of serum PFAS were presented. Logistic regression was performed to confirm the increase in the risk of NAFLD due to changes in PFAS concentration, and the odds ratio and 95% confidence interval (CI) were calculated. Results In both adjusted and unadjusted models, an increased odds ratio was observed with increasing serum concentrations of total PFAS and perfluorooctane sulfonate (PFOS) in the non-obese group. In the adjusted model, the odds ratios for serum total PFAS and PFOS were 6.401 (95% CI: 1.883-21.758) and 7.018 (95% CI: 2.688-18.319). Conclusions In this study, a higher risk of NAFLD based on HSI was associated with serum total PFAS, PFOS in non-obese group. Further research based on radiological or histological evidence for NAFLD diagnosis and long-term prospective studies are necessary. Accordingly, it is necessary to find ways to reduce exposure to PFAS in industry and daily life.
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Affiliation(s)
- Yong Tae Park
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Eui Yup Chung
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Chang Ho Chae
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Young Hoon Lee
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
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Grigorenko EA, Antyukh KY, Rummo OO, Mitkovskaya NP. Modification of Cardiovascular Risk Factors and the Evolution of The Cardiovascular Phenotype of Liver Transplant Recipients in the Long -Term Postoperative Period. KARDIOLOGIIA 2024; 64:25-33. [PMID: 38323441 DOI: 10.18087/cardio.2024.1.n2612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 11/26/2023] [Indexed: 02/08/2024]
Abstract
AIM To evaluate the contribution of traditional and additional cardiovascular risk factors (CVRFs) to the development of chronic ischemic heart disease (CIHD) in liver transplant recipients during the long-term postoperative period. MATERIAL AND METHODS A single-center prospective cohort study was conducted. The study included 740 patients with chronic end-stage liver disease (CESLD) and cirrhotic cardiomyopathy (CCMP). During the observation period (5.4±2.29 years), patients were divided into two groups: liver transplant recipients (n=420) and patients with CESLD on the waiting list who did not receive a donor organ (n=320). In patients enrolled to the study upon inclusion in the waiting list, CVRFs, history, clinical and laboratory and instrumental data were studied at all stages of the hepato-cardiac continuum. RESULTS During the long-term postoperative period, liver transplant recipients belonged to the group of high cardiovascular risk: over a 5-year observation period, 35.7% (n=150) of them developed metabolic syndrome (MS), 9.8% developed verified CIHD associated with MS. The incidence of traditional CVRFs was high (arterial hypertension, 88.6%; obesity, 36.6%; hypercholesterolemia, 77.8%; hypertriglyceridemia, 43.6%; reduced concentration of high-density lipoprotein cholesterol, 35.4%; increased concentrations of low-density lipoprotein cholesterol, 66.8% and very low-density lipoprotein cholesterol, 51.2%; increased atherogenic index, 61.5%). During the long-term postoperative period as compared to the period when patients were on the waiting list, additional CVRFs appeared: increases in body mass index, calcium index, nitric oxide metabolites, endothelin-1, homocysteine, intercellular adhesion molecules VCAM-1 and ICAM-1, and decreases in endothelium-dependent vasodilation and glomerular filtration rate to less than 60 ml/min/1.73 m2. A model for the development of CIHD was created. The model uses a complex of independent risk factors and demonstrates a predictive accuracy of 84.6%. CONCLUSION The study results indicate a modification of CVRFs and a dynamic change in the cardiovascular phenotype of liver transplant recipients: progression of CCMP during their stay on the waiting list, regression of CCMP manifestations during the first 12 months after orthotopic liver transplantation, and increases in the total cardiovascular risk and likelihood of CIHD in the long-term postoperative period.
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Affiliation(s)
- E A Grigorenko
- Republican Scientific and Practical Centre "Cardiology"; Belarusian State Medical University
| | - K Yu Antyukh
- Republican Scientific and Practical Centre "Cardiology"
| | - O O Rummo
- Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
| | - N P Mitkovskaya
- Republican Scientific and Practical Centre "Cardiology"; Belarusian State Medical University
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12
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Hlušička J, Žák A. Dyslipidaemia in Liver Diseases. Folia Biol (Praha) 2024; 70:239-247. [PMID: 39889216 DOI: 10.14712/fb2024070050239] [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] [Indexed: 02/02/2025]
Abstract
The liver is the central organ in lipid metabolism and plays a key role in a variety of biochemical processes. It is involved in lipoprotein synthesis, fatty acid beta oxidation, ketone body production, cholesterol synthesis, bile production, and storage and mobilization of lipids. Metabolic diseases such as obesity, type 2 diabetes mellitus and certain dyslipidaemias can lead to chronic liver conditions, especially non-alcoholic fatty liver disease. Conversely, chronic liver diseases such as liver cirrhosis and chronic cholestasis can induce dyslipidaemias. This review provides a comprehensive biochemical and clinical overview of the intricate relationship between the lipid-lipoprotein metabolism and chronic liver diseases, including non-alcoholic fatty liver disease, cholestasis, alcohol-related liver disease, viral hepatitis and cirrhosis, all of which have been selected due to their importance in current clinical practice. These conditions not only affect liver function but also have widespread metabolic implications critical for patient management and therapeutic strategies. In addition to discussing the clinical manifestations and pathophysiology of liver diseases, this review delves into the genetic and non-genetic factors that influence their development and progression. By bridging clinical observations with biochemical me-chanisms, this review aims to improve the understan-ding of how lipid metabolism disorders contribute to chronic liver diseases and to identify potential targets for therapeutic intervention.
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Affiliation(s)
- Jiří Hlušička
- 4th Department of Medicine - Department of Gastroenterology and Hepatology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czech Republic.
| | - Aleš Žák
- 4th Department of Medicine - Department of Gastroenterology and Hepatology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czech Republic
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13
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Gora AH, Rehman S, Dias J, Fernandes JMO, Olsvik PA, Sørensen M, Kiron V. Microbial oil, alone or paired with β-glucans, can control hypercholesterolemia in a zebrafish model. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159383. [PMID: 37657755 DOI: 10.1016/j.bbalip.2023.159383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/12/2023] [Accepted: 08/29/2023] [Indexed: 09/03/2023]
Abstract
Dyslipidemia is often associated with unhealthy dietary habits, and many mammalian studies have explored the mode of action of certain bioactive compounds such as β-glucans and n-3 PUFAs to understand their potential to normalize the lipid metabolism. There are only a few investigations that adopted omic approaches to unveil their combined effect on hypercholesterolemia. Zebrafish (Danio rerio) was used as a model organism to reveal the efficacy of Schizochytrium oil and β-glucans (from Euglena gracilis and Phaeodactylum tricornutum) against cholesterol-rich diet induced dyslipidemia. One of the folowing four diets was fed to a particular group of fish: a control high-cholesterol diet, a Schizochytrium oil diet or one of the two diets containing the oil and β-glucan. The plasma HDL, expression of hepatic genes linked to, among others, ferric ion binding and plasma phosphatidylcholines were higher and plasma cholesterol esters and triacylglycerols were lower in the microbial oil-fed fish compared to the fish fed high cholesterol diet. While the fish fed a mix of microbial oil and Euglena β-glucan had lower plasma triacylglycerols and expression of hepatic genes linked to PPAR signaling pathway and enriched biosynthesis of plasma unsaturated fatty acids, the fish fed microbial oil-Phaeodactylum β-glucan combination had lower abundance of triacylglycerols rich in saturated and mono-unsaturated fatty acids and cholesterol esters in the plasma.
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Affiliation(s)
- Adnan H Gora
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Saima Rehman
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | | | | | - Pål A Olsvik
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Mette Sørensen
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Viswanath Kiron
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway.
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14
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Sequeira C, Coelho M, Costa Santos I, Ramos Lopes S, Mangualde J, Oliveira AP. Severe Hypercholesterolemia Mediated by Lipoprotein X in an Immunosuppressed Patient: A Case Report. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2023; 30:398-402. [PMID: 37868638 PMCID: PMC10586217 DOI: 10.1159/000526854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 08/10/2022] [Indexed: 10/24/2023]
Abstract
Cholestatic liver diseases may be associated with increased plasmatic cholesterol due to an abnormal lipoprotein - lipoprotein X (LpX). Correcting the underlying cause of cholestasis is the critical treatment of LpX-associated hypercholesterolemia without any proven benefit from conventional lipid-lowering agents. In some situations, plasma exchange may apply to prevent associated complications, such as hyperviscosity syndrome. The authors present the case of a 44-year-old man with orbital inflammatory pseudotumor on prednisolone, admitted due to hepatocellular and cholestatic lesion and severe hypercholesterolemia. Laboratory investigation established that hepatitis E virus was responsible for liver injury and showed that LpX mediated the severe hypercholesterolemia. Reduction of the immunosuppressive load contributed to virus clearance. The consequent resolution of cholestasis and cholesterol removal by plasmapheresis allowed lipid profile normalization. The authors report the first case of LpX-associated hypercholesterolemia in a patient with hepatitis E-induced cholestasis and revisit the role of the liver in lipid metabolism.
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Affiliation(s)
- Cristiana Sequeira
- Gastroenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
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15
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Parhofer KG, Laufs U. Lipid Profile and Lipoprotein(a) Testing. DEUTSCHES ARZTEBLATT INTERNATIONAL 2023; 120:582-588. [PMID: 37403458 PMCID: PMC10552634 DOI: 10.3238/arztebl.m2023.0150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 06/07/2023] [Accepted: 06/07/2023] [Indexed: 07/06/2023]
Abstract
BACKGROUND The treatment of dyslipidemias plays a major role in the primary and secondary prevention of cardiovascular disease. Proper evaluation of the patient's lipid status is very important for risk assessment and as a guide to treatment. METHODS This review is based on publications retrieved by a selective search of the literature, including current guidelines. RESULTS Measurement of the plasma concentration of cholesterol, triglycerides, HDL- and LDL-cholesterol, calculation of the non-HDL cholesterol concentration, and-on a single occasion-determination of the lipoprotein (a) concentration enable the clinician to quantify the lipid-associated health risk and monitor the effects of treatment. These blood tests can be performed in a non-fasting state except in special situations (particularly, hypertriglyceridemia). The HDL quotient is an obsolete measure. The main goal of treatment is to achieve an LDL-cholesterol level adequate to the patient's cardiovascular risk through lifestyle modification and, if necessary, medication. A high lipoprotein (a) concentration cannot be lowered with orally administered drugs; above all, patients should lower their LDL-cholesterol levels while minimizing all other risk factors. CONCLUSION Measurement of the concentration of cholesterol, triglycerides, and HDL- and LDL-cholesterol and calculation of the non-HDL-C suffice as a guide to lipid-lowering treatment. The primary therapeutic goal is to lower LDL cholesterol.
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Affiliation(s)
- Klaus G. Parhofer
- Department of Internal Medicine IV– Großhadern, LMU Hospital, Munich, Germany
| | - Ulrich Laufs
- Department of Cardiology, University Hospital of Leipzig, Leipzig, Germany
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16
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Ng CH, Tang ASP, Xiao J, Wong ZY, Yong JN, Fu CE, Zeng RW, Tan C, Wong GHZ, Teng M, Chee D, Tan DJH, Chan KE, Huang DQ, Chew NW, Nah B, Siddqui MS, Sanyal AJ, Noureddin M, Muthiah M. Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals. Hepatol Commun 2023; 7:e0005. [PMID: 36757421 PMCID: PMC9915961 DOI: 10.1097/hc9.0000000000000005] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/18/2022] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND AND AIMS Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.
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Affiliation(s)
- Cheng Han Ng
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ansel Shao Pin Tang
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jieling Xiao
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhen Yu Wong
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jie Ning Yong
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Clarissa E. Fu
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rebecca W. Zeng
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Caitlyn Tan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gabriel Hong Zhe Wong
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Margaret Teng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Darren Jun Hao Tan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai En Chan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Daniel Q. Huang
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Nicholas W.S. Chew
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore
| | - Benjamin Nah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Mohammad S. Siddqui
- Division of Gastroenterology, Department of Internal Medicine, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Department of Internal Medicine, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Mark Muthiah
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
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17
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Girard J, Wagner C, Ravi S, Agarwal M, Bril F. Hypercholesterolemia After COVID-19: Time to Include Lipoprotein X Among the Differential Diagnoses. AACE Clin Case Rep 2023; 9:35-38. [PMID: 36643829 PMCID: PMC9824939 DOI: 10.1016/j.aace.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/23/2022] [Accepted: 01/04/2023] [Indexed: 01/08/2023] Open
Abstract
Background Lipoprotein X (LpX) is an abnormal lipoprotein composed of phospholipids, free cholesterol, and albumin. Its overaccumulation is an infrequent cause of hyperlipidemia, which oftentimes presents in patients with cholestatic liver disease. The aim is to present the first 2 cases of patients with post-COVID cholangiopathy and LpX overaccumulation. Case Report We present 2 female patients (ie, a 34-year-old [patient 1] and a 56-year-old [patient 2]), who had complicated courses of COVID-19, requiring prolonged mechanical ventilation (>4 weeks). One month after discharge, patient 1 presented with abdominal pain. Patient 2 had gangrenous cholecystitis and later developed recurrent elevation of alkaline phosphatase and bilirubin. Both patients were diagnosed with cholestatic liver disease. During outpatient follow-up both patients were found to have elevated plasma low-density lipoprotein cholesterol (LDL-C) in routine lipid panels (723 mg/dL and 1389 mg/dL, respectively). Both patients underwent various treatments for elevated LDL-C before referral to endocrinology. Patients were diagnosed with LpX overaccumulation from post-COVID-19 cholangiopathy. In both patients, LDL-C fluctuations seen in routine lipid panels (affected by LpX levels) were tightly correlated with changes in alkaline phosphate and bilirubin. Discussion Our patients represent the first report of LpX overaccumulation in patients with post-COVID-19 cholangiopathy. Whether LpX accumulation is only the result of liver dysfunction, or COVID-19 infection plays a direct role in elevated LpX levels is still unknown. Conclusion In patients with complicated courses of COVID-19, LpX overaccumulation should be considered when a routine lipid panel shows significant LDL-C elevations. Awareness among health care providers regarding LpX is important to avoid unnecessary workup and treatment.
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Affiliation(s)
- Jennifer Girard
- Division of Internal Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Courtney Wagner
- Division of Internal Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Sujan Ravi
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Monica Agarwal
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Division of Endocrinology, Diabetes and Metabolism, Birmingham VA Medical Center, Birmingham, Alabama
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Division of Endocrinology, Diabetes and Metabolism, Birmingham VA Medical Center, Birmingham, Alabama
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18
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Maklakova SY, Lopukhov AV, Khudyakov AD, Kovalev SV, Mazhuga MP, Chepikova OE, Zamyatnin AA, Majouga AG, Klyachko NL, Beloglazkina EK. Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability. RSC Med Chem 2023; 14:56-64. [PMID: 36760736 PMCID: PMC9890652 DOI: 10.1039/d2md00119e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022] Open
Abstract
Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered as a way to reduce unwanted side effects. Herein we report on synthesis and evaluation of atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor (ASGPR). The prepared conjugates showed greater water solubility compared to unmodified atorvastatin. The synthesised compounds demonstrated potent binding to the ASGPR with submicromolar K D values. The conjugates with an amide bond connecting atorvastatin and the targeting moiety displayed the optimal stability under model conditions, as they underwent hydrolysis only when incubated with the intracellular protease. The hydrolysis products effectively inhibited HMG-R activity. The results suggest that the designed amide-based compounds have the potential to be further developed as orally administered prodrugs of atorvastatin.
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Affiliation(s)
- Svetlana Yu Maklakova
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Anton V Lopukhov
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Alexandr D Khudyakov
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Sergey V Kovalev
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Maria P Mazhuga
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Olga E Chepikova
- Department of Biotechnology, Sirius University of Science and Technology Olympic Avenue 1 Sochi 354340 Russian Federation
| | - Andrey A Zamyatnin
- Department of Biotechnology, Sirius University of Science and Technology Olympic Avenue 1 Sochi 354340 Russian Federation
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University Trubetskaya Street 8/2 Moscow 119991 Russian Federation
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University GSP-1, Leninskie Gory Moscow 119992 Russian Federation
- Faculty of Health and Medical Sciences, University of Surrey Guildford GU2 7XH UK
| | - Alexander G Majouga
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
- Dmitry Mendeleev University of Chemical Technology of Russia Miusskaya Square 9 Moscow 125047 Russian Federation
| | - Natalia L Klyachko
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
| | - Elena K Beloglazkina
- Chemistry Department, Lomonosov Moscow State University GSP-1, Leninskie Gory 1/3 Moscow 119991 Russian Federation
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Reshetnyak VI, Maev IV. Features of Lipid Metabolism Disorders in Primary Biliary Cholangitis. Biomedicines 2022; 10:3046. [PMID: 36551803 PMCID: PMC9775928 DOI: 10.3390/biomedicines10123046] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/15/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune liver disease that mostly affects women. A progressive disorder in the processes of bile secretion and enterohepatic bile salts circulation in patients with PBC already in its early stages, leading to an insufficient release of bile acids into the bowel and their entry into the systemic circulation. Insufficient bile acids released into the duodenum contributes to the development of malabsorption, energy malnutrition, and slowly progressive weight loss. The pathophysiological mechanisms of weight loss and its slow progression are associated with the deterioration of the fat emulsification processes and with the reduced absorption of hydrolyzed products, such as fatty acids and monoglycerides, with steatorrhea in patients with PBC, as well as in those with gut dysbiosis. Just in the early stages of the disease, this results in accelerated fatty acid β-oxidation that is aimed at compensating for progressive energy malnutrition. The entry of bile acids into the systemic circulation in PBC is accompanied by dyslipidemia. The mechanism of hyperlipidemia in patients with PBC differs from that in other conditions because along with an increase in total cholesterol (TC), there are elevated high-density lipoprotein levels and the appearance of unusual lipoprotein X (Lp-X). The appearance of Lp-X is most likely to be the body's protective reaction to inactivate the detergent effect of bile acids on the membrane structures of blood corpuscles and vascular endothelial cells. It is bile acids, rather than TC levels, that correlate with the content of Lp-X and determine its formation. Concomitant hypercholesterolemia in patients with PBC is also aimed at neutralizing the detergent effect of bile acids that have entered the systemic circulation and is most likely a compensatory reaction of the body. "Anomalous" hypercholesterolemia in PBC can serve as a model system for the search and development of new methods for the treatment of dyslipidemia since it occurs without an increase in the incidence of cardiovascular events.
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Affiliation(s)
- Vasiliy I. Reshetnyak
- Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
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20
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Hashem AM, Cifuentes L, Calderon G, Ricardo-Silgado ML, Gonzalez-Izundegui D, Campos A, McRae A, Franks S, Hurtado MD, Burton D, Petterson XM, Lanza IR, Camilleri M, Acosta A. Effect of caloric intake and macronutrient composition on intestinal cholesterol absorption and bile acids in patients with obesity. Am J Physiol Gastrointest Liver Physiol 2022; 323:G157-G164. [PMID: 35727128 PMCID: PMC9377780 DOI: 10.1152/ajpgi.00108.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 01/31/2023]
Abstract
Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction among dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-wk nutritional intervention nonrandomized clinical trial with three different sequential diets for a week in the following order: regular diet (RD); high calorie, high-fat diet (HCHF), washout period on RD; and low-calorie, low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study [n = 8 normal weight (NW); n = 8 with obesity (OB)]. Overall, there was a significant increase in intestinal cholesterol uptake when changing from RD to HCHF and a reduction in intestinal cholesterol uptake from HCHF to LCLF. When analyzing by BMI groups, these findings were similar in patients with NW (RD to HCHF: P < 0.007; HCHF to LCLF: P = 0.02); however, in patients with obesity, the change in intestinal cholesterol uptake was only observed when changing from RD to HCHF (P = 0.006). There was no correlation between cholesterol absorption and fecal bile acids or other markers of BA metabolism in all patients or the subgroups. Dietary caloric content had a significant effect on cholesterol absorption, however, this effect is blunted in patients with obesity. These data are consistent with the impaired effect of a low-fat diet on cholesterol absorption in obesity.NEW & NOTEWORTHY We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.
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Affiliation(s)
- Anas Mohamad Hashem
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Lizeth Cifuentes
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Gerardo Calderon
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Maria Laura Ricardo-Silgado
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Daniel Gonzalez-Izundegui
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alejandro Campos
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alison McRae
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Shawna Franks
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Maria Daniela Hurtado
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic Health System, La Crosse, Wisconsin
| | - Duane Burton
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Ian R Lanza
- Metabolomics Core Laboratory, Mayo Clinic, Rochester, Minnesota
- Endocrinology Research Unit, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Michael Camilleri
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
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21
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Yamauchi R, Takata K, Fukunaga A, Tanaka T, Yokoyama K, Shakado S, Nabeshima K, Yoshimitsu K, Hirai F. Improvement of vanishing bile duct syndrome with hyperlipidemia. Clin J Gastroenterol 2022; 15:784-790. [DOI: 10.1007/s12328-022-01650-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022]
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22
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When LDL Cholesterol Is Not LDL Cholesterol: LpX, A Clinical Lesson. JACC Case Rep 2022; 4:690-693. [PMID: 35677796 PMCID: PMC9168776 DOI: 10.1016/j.jaccas.2022.03.009] [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] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/15/2022] [Accepted: 03/07/2022] [Indexed: 11/20/2022]
Abstract
LpX is a lipoprotein formed in cholestatic conditions and often erroneously reported as LDL-C. A low ApoB level can support the diagnosis of LpX. Treatment should not automatically focus on lowering serum lipid levels, but primarily on resolving the cause of cholestasis. (Level of Difficulty: Advanced.)
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23
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Tada MT, Rocha VZ, Lima IR, Oliveira TGM, Chacra AP, Miname MH, Nunes VS, Nakandakare ER, Costa Gurgel Castelo MH, Jannes CE, Santos RD, Krieger JE, Pereira AC. Screening of
ABCG5
and
ABCG8
Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program. Circ Genom Precis Med 2022; 15:e003390. [DOI: 10.1161/circgen.121.003390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background:
Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in
ABCG5/ABCG8
. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program.
Methods:
From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the
ABCG5/8
genes. Clinical and laboratory characteristics of affected individuals were determined.
Results:
Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for
ABCG5/ABCG8
genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean β-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122–521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities.
Conclusions:
Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
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Affiliation(s)
- Mauricio Teruo Tada
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
| | - Viviane Zorzanelli Rocha
- Lipid Clinic, Heart Institute (InCor) (V.Z.R., A.P.C., M.H.M., R.D.S.), University of São Paulo Medical School Hospital
| | - Isabella Ramos Lima
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
| | - Théo Gremen Mimary Oliveira
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
| | - Ana Paula Chacra
- Lipid Clinic, Heart Institute (InCor) (V.Z.R., A.P.C., M.H.M., R.D.S.), University of São Paulo Medical School Hospital
| | - Marcio Hiroshi Miname
- Lipid Clinic, Heart Institute (InCor) (V.Z.R., A.P.C., M.H.M., R.D.S.), University of São Paulo Medical School Hospital
| | - Valéria Sutti Nunes
- Laboratório de Lípides (LIM10), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo (V.S.N., E.R.N.)
| | - Edna Regina Nakandakare
- Laboratório de Lípides (LIM10), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo (V.S.N., E.R.N.)
| | | | - Cinthia Elim Jannes
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
| | - Raul D. Santos
- Lipid Clinic, Heart Institute (InCor) (V.Z.R., A.P.C., M.H.M., R.D.S.), University of São Paulo Medical School Hospital
- Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil (R.D.S.)
| | - José Eduardo Krieger
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
| | - Alexandre Costa Pereira
- Laboratory of Genetics and Molecular Cardiology (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.), University of São Paulo Medical School Hospital
- Genetics Department, Harvard Medical School, Boston, MA (A.C.P.)
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24
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Seetlani NK, Kumari G, Yasmin F, Hasan CA, Hussaini M, Awan S, Mubeen KI, Jabeen R, Ansari S, Siddiqui SA, Aziz DM, Farooque U. The frequency and pattern of deranged lipid profile in patients with ischemic stroke: a retrospective study. ACTA BIO-MEDICA : ATENEI PARMENSIS 2022; 93:e2022178. [PMID: 35775784 PMCID: PMC9335412 DOI: 10.23750/abm.v93i3.11576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/31/2021] [Indexed: 11/26/2022]
Abstract
Ischemic Stroke has been recognized as the principal cause of disability and the third leading cause of mortality worldwide. The aim of this study was to determine the frequency and pattern of dyslipidemia in patients presenting with ischemic stroke at a tertiary care hospital in Karachi, Pakistan and to evaluate the effect of demographic and clinical factors on the frequency and pattern of dyslipidemia in ischemic stroke subjects. Methods: A cross-sectional study carried on a sample size of 235 patients presenting to the out-patient clinic with paralysis, difficulty in speech, and/or loss of consciousness lasting for one hour or more. Blood samples were analyzed for total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and high-density lipoproteins (HDL) by the enzymatic colorimetric methodology. These values were recorded on the pre-defined proforma by the investigators. All analysis was performed using SPSS version 23.0. Results: The average age of the patients was 50.84±11.51 years and 62.1% of them were males. The frequency of dyslipidemia was observed in more than half (n=134/235, 57.02%) of ischemic stroke patients. Regarding the dyslipidemia pattern, TC, VLDL-C and TG levels were deranged in more than 50% of the cases. The most commonly deranged values were of TC and VLDL-C, followed by TG levels. It was observed that patients with a previous history of DM (73.9%, p=0.002) and HTN (81.3%, p=0.001) had significantly higher rates of deranged lipid profiles. Lipid values were found to be more deranged in patients aged 41-50 years (p=0.002) however, no statistically significant differences were observed with respect to BMI (p=0.192) and symptoms duration (p=0.334). Conclusions: Dyslipidemia is an important risk factor for ischemic stroke, and elevated LDL-C is usually the lipid fraction implicated in the pathologic mechanism of stroke.
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Affiliation(s)
- Naresh Kumar Seetlani
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Geeta Kumari
- Department of Internal Medicine, Dow University of Health Sciences
| | - Farah Yasmin
- Department of Internal Medicine, Dow University of Health Sciences
| | | | - Maheen Hussaini
- Department of Internal Medicine, Dow University of Health Sciences
| | - Sana Awan
- Department of Internal Medicine, Dow University of Health Sciences
| | - Khalid Imran Mubeen
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Rakshinda Jabeen
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Sadia Ansari
- Department of Internal Medicine, Dow University of Health Sciences
| | | | - Dr Momin Aziz
- Department of Internal Medicine, Dow University of Health Sciences
| | - Umer Farooque
- Department of Neurology, Dow University of Health Sciences, Karachi, Pakistan
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25
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Zhang S, Hong F, Ma C, Yang S. Hepatic Lipid Metabolism Disorder and Atherosclerosis. Endocr Metab Immune Disord Drug Targets 2021; 22:590-600. [PMID: 34931971 DOI: 10.2174/1871530322666211220110810] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/28/2021] [Accepted: 11/01/2021] [Indexed: 11/22/2022]
Abstract
Lipid metabolism disorder plays a fundamental role in the pathogenesis of atherosclerosis. As the largest metabolic organ of the human body, liver has a key role in lipid metabolism by influencing fat production, fat decomposition, and the intake and secretion of serum lipoproteins. Numerous clinical and experimental studies have indicated that the dysfunction of hepatic lipid metabolism is closely tied to the onset of atherosclerosis. However, the identity and functional role of hepatic lipid metabolism responsible for these associations remain unknown. This review presented that cholesterol synthesis, cholesterol transport, and the metabolism of triglyceride, lipoproteins, and fatty acids are all associated with hepatic lipid metabolism and atherosclerosis. Moreover, we also discussed the roles of gut microbiota, inflammatory response, and oxidative stress in the pathological association between hepatic lipid metabolism and atherosclerosis. These significant evidences support strongly that hepatic lipid metabolism disorders may increase the risk of atherosclerosis.
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Affiliation(s)
- Sen Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
| | - Fenfang Hong
- Experimental Center of Pathogen Biology, Nanchang University, Nanchang, China
| | - Chen Ma
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
| | - Shulong Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
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26
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Adimulam T, Abdul N, Chuturgoon A. HepG2 liver cells treated with fumonisin B1 in galactose supplemented media have altered expression of genes and proteins known to regulate cholesterol flux. WORLD MYCOTOXIN J 2021. [DOI: 10.3920/wmj2021.2723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Fumonisin B1 (FB1) contributes to mycotoxicosis in animals and has been associated with the incidence of some cancers in humans. The effect of FB1 on lipidomic profiles, sphingolipids and cholesterol levels have been demonstrated in experimental models, however, the events leading to altered cholesterol levels are unclear. This study investigates the molecular mechanisms that regulate the effect of FB1 on cholesterol homeostasis in galactose supplemented HepG2 liver cells. Galactose supplementation is a proven method utilised to circumvent the Crabtree effect exhibited by cancer cells, which forces cancer cells to activate the mitochondria. HepG2 cells were cultured in galactose supplemented media and treated with FB1 (IC50 = 25 μM) for 6 h. Cell viability was determined using the MTT assay. Metabolic status was evaluated using ATP luciferase assay, and cholesterol regulatory transcription factors (SIRT1, SREBP-1C, LXR, LDLR, PCSK9, and ABCA1) were investigated using western blotting and qPCR. FB1 in galactose supplemented HepG2 cells increased gene expression of SIRT1 (P<0.05), SREBP-1C, LXR, and LDLR; however, PCSK9 (P<0.05) was decreased. Furthermore, protein expression of SIRT1, LXR, and LDLR was elevated upon FB1 treatment, while SREBP-1C and PCSK9 were reduced. The data provides evidence that SIRT1 reduced the expression of PCSK9 and deacetylated LXR to prevent degradation of LDLR. This could result in a dysregulated cholesterol flux, which may contribute to FB1 mediated toxicity.
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Affiliation(s)
- T. Adimulam
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
| | - N.S. Abdul
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
- Applied Microbial and Health Biotechnology Institute, Cape Peninsula University of Technology, Cape Town 7535, South Africa
| | - A.A. Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
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27
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Jeyaraj R, Bounford KM, Ruth N, Lloyd C, MacDonald F, Hendriksz CJ, Baumann U, Gissen P, Kelly D. The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges. Genes (Basel) 2021; 12:1837. [PMID: 34828443 PMCID: PMC8621872 DOI: 10.3390/genes12111837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/26/2022] Open
Abstract
Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010-2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.
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Affiliation(s)
- Rebecca Jeyaraj
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK;
| | - Kirsten McKay Bounford
- West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK;
| | - Nicola Ruth
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Carla Lloyd
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Fiona MacDonald
- West Midlands Regional Genetics Service, Birmingham Women’s and Children’s Hospital, Birmingham B15 2TG, UK;
| | - Christian J. Hendriksz
- Steve Biko Academic Unit, Level D3 New Pretoria Academic Hospital, Malherbe Street, Pretoria 0002, South Africa;
| | - Ulrich Baumann
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany
| | - Paul Gissen
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
| | - Deirdre Kelly
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
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28
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Sun P, Zhao L, Zhang N, Zhou J, Zhang L, Wu W, Ji B, Zhou F. Bioactivity of Dietary Polyphenols: The Role in LDL-C Lowering. Foods 2021; 10:2666. [PMID: 34828946 PMCID: PMC8617782 DOI: 10.3390/foods10112666] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/27/2021] [Accepted: 10/31/2021] [Indexed: 12/18/2022] Open
Abstract
Cardiovascular diseases are the leading causes of the death around the world. An elevation of the low-density lipoprotein cholesterol (LDL-C) level is one of the most important risk factors for cardiovascular diseases. To achieve optimal plasma LDL-C levels, clinal therapies were investigated which targeted different metabolism pathways. However, some therapies also caused various adverse effects. Thus, there is a need for new treatment options and/or combination therapies to inhibit the LDL-C level. Dietary polyphenols have received much attention in the prevention of cardiovascular diseases due to their potential LDL-C lowering effects. However, the effectiveness and potential mechanisms of polyphenols in lowering LDL-C is not comprehensively summarized. This review focused on dietary polyphenols that could reduce LDL-C and their mechanisms of action. This review also discussed the limitations and suggestions regarding previous studies.
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Affiliation(s)
- Peng Sun
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
| | - Liang Zhao
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, China;
| | - Nanhai Zhang
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
| | - Jingxuan Zhou
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
| | - Liebing Zhang
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
| | - Wei Wu
- College of Engineering, China Agricultural University, Beijing 100083, China;
| | - Baoping Ji
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
| | - Feng Zhou
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (P.S.); (N.Z.); (J.Z.); (L.Z.); (B.J.)
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29
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Palikova M, Kopp R, Kohoutek J, Blaha L, Mares J, Ondrackova P, Papezikova I, Minarova H, Pojezdal L, Adamovsky O. Cyanobacteria Microcystis aeruginosa Contributes to the Severity of Fish Diseases: A Study on Spring Viraemia of Carp. Toxins (Basel) 2021; 13:601. [PMID: 34564605 PMCID: PMC8473110 DOI: 10.3390/toxins13090601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 11/28/2022] Open
Abstract
Fish are exposed to numerous stressors in the environment including pollution, bacterial and viral agents, and toxic substances. Our study with common carps leveraged an integrated approach (i.e., histology, biochemical and hematological measurements, and analytical chemistry) to understand how cyanobacteria interfere with the impact of a model viral agent, Carp sprivivirus (SVCV), on fish. In addition to the specific effects of a single stressor (SVCV or cyanobacteria), the combination of both stressors worsens markers related to the immune system and liver health. Solely combined exposure resulted in the rise in the production of immunoglobulins, changes in glucose and cholesterol levels, and an elevated marker of impaired liver, alanine aminotransferase (ALT). Analytical determination of the cyanobacterial toxin microcystin-LR (MC-LR) and its structurally similar congener MC-RR and their conjugates showed that SVCV affects neither the levels of MC in the liver nor the detoxification capacity of the liver. MC-LR and MC-RR were depurated from liver mostly in the form of cysteine conjugates (MC-LR-Cys, MC-RR-Cys) in comparison to glutathione conjugates (LR-GSH, RR-GSH). Our study brought new evidence that cyanobacteria worsen the effect of viral agents. Such inclusion of multiple stressor concept helps us to understand how and to what extent the relevant environmental stressors co-influence the health of the fish population.
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Affiliation(s)
- Miroslava Palikova
- Department of Ecology and Diseases of Zoo Animals, Game, Fish and Bees, Faculty of Veterinary Hygiene and Ecology, University of Veterinary Sciences Brno, 61242 Brno, Czech Republic; (M.P.); (I.P.); (H.M.)
- Department of Zoology, Fisheries, Hydrobiology and Apiculture, Faculty of Agronomy, Mendel University in Brno, 61300 Brno, Czech Republic; (R.K.); (J.M.)
| | - Radovan Kopp
- Department of Zoology, Fisheries, Hydrobiology and Apiculture, Faculty of Agronomy, Mendel University in Brno, 61300 Brno, Czech Republic; (R.K.); (J.M.)
| | - Jiri Kohoutek
- RECETOX (Research Centre for Toxic Compounds in the Environment), Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (J.K.); (L.B.)
| | - Ludek Blaha
- RECETOX (Research Centre for Toxic Compounds in the Environment), Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (J.K.); (L.B.)
| | - Jan Mares
- Department of Zoology, Fisheries, Hydrobiology and Apiculture, Faculty of Agronomy, Mendel University in Brno, 61300 Brno, Czech Republic; (R.K.); (J.M.)
| | - Petra Ondrackova
- Department of Infectious Diseases and Preventive Medicine, Veterinary Research Institute, 62100 Brno, Czech Republic; (P.O.); (L.P.)
| | - Ivana Papezikova
- Department of Ecology and Diseases of Zoo Animals, Game, Fish and Bees, Faculty of Veterinary Hygiene and Ecology, University of Veterinary Sciences Brno, 61242 Brno, Czech Republic; (M.P.); (I.P.); (H.M.)
- Department of Zoology, Fisheries, Hydrobiology and Apiculture, Faculty of Agronomy, Mendel University in Brno, 61300 Brno, Czech Republic; (R.K.); (J.M.)
| | - Hana Minarova
- Department of Ecology and Diseases of Zoo Animals, Game, Fish and Bees, Faculty of Veterinary Hygiene and Ecology, University of Veterinary Sciences Brno, 61242 Brno, Czech Republic; (M.P.); (I.P.); (H.M.)
- Department of Infectious Diseases and Preventive Medicine, Veterinary Research Institute, 62100 Brno, Czech Republic; (P.O.); (L.P.)
| | - Lubomir Pojezdal
- Department of Infectious Diseases and Preventive Medicine, Veterinary Research Institute, 62100 Brno, Czech Republic; (P.O.); (L.P.)
| | - Ondrej Adamovsky
- RECETOX (Research Centre for Toxic Compounds in the Environment), Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (J.K.); (L.B.)
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30
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Zhao Y, Wang S, Liang S, Zhang H, Zhang Y, Yu R, Zhang K, Huang H, Dong J, Gan W. Clinical laboratory characteristics of patients with obstructive jaundice accompanied by dyslipidemia. Clin Biochem 2021; 94:42-47. [PMID: 33894198 DOI: 10.1016/j.clinbiochem.2021.04.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 04/16/2021] [Accepted: 04/18/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Abnormal lipid metabolism manifests as hypercholesterolemia in patients with obstructive jaundice due to lipoprotein X (LpX). Our aim was to explore the clinical laboratory characteristics of patients with obstructive jaundice accompanied by dyslipidemia in a large number of samples. METHODS A total of 665 patients with obstructive jaundice were included and categorized into two groups (with/without dyslipidemia) based on the ratio of the sum of HDL-c and LDL-c to total cholesterol [(HDL-c + LDL-c)/TC] with a cut-off value of 0.695. Laboratory liver, kidney, and blood lipid parameters were determined. Cholesterol composition assessment was performed by ultracentrifugation and high-performance liquid chromatography (UC-HPLC), and serum protein profiles were analyzed by capillary electrophoresis. RESULTS Liver function in patients with obstructive jaundice accompanied by dyslipidemia was more aggravated than that in patients with simple obstructive jaundice (P < 0.05). The (HDL-c + LDL-c)/TC ratio was negatively correlated with bilirubin levels (P < 0.05). In addition, the difference in ApoB/LDL-c ratios was statistically significant between the obstructive jaundice accompanied by dyslipidemia group and healthy control group (P < 0.05). The LDL-c concentration determined by the UC-HPLC method was more than five times that determined by the enzymatic method (P < 0.05). Bisalbuminemia was found in 43 of 60 patients with obstructive jaundice accompanied by hypercholesterolemia. CONCLUSIONS In patients with obstructive jaundice, the decreased (HDL-c + LDL-c)/TC ratio may be a novel marker to identify dyslipidemia secondary to LpX. The decreased ratio was associated with poor liver function and indicated disease progression.
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Affiliation(s)
- Yanhua Zhao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Siming Wang
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
| | - Shanshan Liang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - He Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanxing Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rui Yu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Keyi Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hengjian Huang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jun Dong
- MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China.
| | - Wei Gan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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31
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An observational study on the effect of hypercholesterolemia developed after living donor liver transplantation on cardiac event and graft failure. Sci Rep 2021; 11:959. [PMID: 33441656 PMCID: PMC7806822 DOI: 10.1038/s41598-020-79673-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 12/10/2020] [Indexed: 11/08/2022] Open
Abstract
This study sought to evaluate the association between newly-developed significant hypercholesterolemia within one year following living donor liver transplantation (LDLT) and long term outcomes in light of cardiovascular events and graft failure. From October 2003 to July 2017, 877 LDLT recipients were stratified according to development of significant hypercholesterolemia within one year following LDLT. The primary outcome was occurrence of a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and coronary revascularization after LDLT. The incidence of graft failure, defined as all-cause death or retransplantation, was also compared. A total of 113 (12.9%) recipients developed significant hypercholesterolemia within one year. The differences in incidences of cardiac related events and graft related events began emerging significantly higher in the hypercholesterolemia group after 24 months and 60 months since the LDLT, respectively. After adjustment using the inverse probability of weighting, the hazard ratio (HR) for MACE was 2.77 (95% confidence interval (CI) 1.16–6.61; p = 0.02), while that for graft failure was 3.76 (95% CI 1.97–7.17, p < 0.001). A significant hypercholesterolemia after LDLT may be associated with cardiac and graft-related outcome; therefore, a further study and close monitoring of cholesterol level after LDLT is needed.
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32
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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: 69] [Impact Index Per Article: 13.8] [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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Abstract
CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.
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Affiliation(s)
| | - Peter Wiesli
- Endokrinologie/Diabetologie, Kantonsspital Frauenfeld
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34
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Küçükçongar Yavaş A, Çavdarlı B, Ünal Uzun Ö, Uncuoğlu A, Gündüz M. A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis. J Pediatr Endocrinol Metab 2020; 33:665-669. [PMID: 32229667 DOI: 10.1515/jpem-2019-0314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/03/2020] [Indexed: 12/15/2022]
Abstract
Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.
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Affiliation(s)
- Aynur Küçükçongar Yavaş
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Büşra Çavdarlı
- Medical Genetics, Ministry of Health, Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Özlem Ünal Uzun
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Ayşen Uncuoğlu
- Pediatric Gastroenterology, Sakarya University, Sakarya, Turkey
| | - Mehmet Gündüz
- Pediatric Metabolism, Ministry of Health Ankara City Hospital, University of Health Science, Ankara, Turkey
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35
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Tardelli M, Bruschi FV, Fuchs CD, Claudel T, Auer N, Kunczer V, Baumgartner M, A.H.O. Ronda O, Verkade HJ, Stojakovic T, Scharnagl H, Habib A, Zimmermann R, Lotersztajn S, Trauner M. Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis. Hepatology 2020; 71:1750-1765. [PMID: 31505038 PMCID: PMC7317927 DOI: 10.1002/hep.30929] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 08/29/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. APPROACH AND RESULTS To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL-/- ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2-/- ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL-/- mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2-/- mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation. CONCLUSIONS Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.
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Affiliation(s)
- Matteo Tardelli
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Francesca V. Bruschi
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Claudia D. Fuchs
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Nicole Auer
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Victoria Kunczer
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Maximilian Baumgartner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Onne A.H.O. Ronda
- Center for Liver, Digestive and Metabolic DiseasesDepartments of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Henk Jan Verkade
- Center for Liver, Digestive and Metabolic DiseasesDepartments of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsUniversity Hospital GrazGrazAustria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
| | - Aida Habib
- Université de ParisCentre de Recherche sur l'InflammationINSERMUMR1149CNRSERL 8252ParisFrance
- Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon
| | | | - Sophie Lotersztajn
- Université de ParisCentre de Recherche sur l'InflammationINSERMUMR1149CNRSERL 8252ParisFrance
| | - Michael Trauner
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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36
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Kim HN, Jeon DG, Lim Y, Jang IS. The effects of coenzyme Q 10 supplement on blood lipid indices and hepatic antioxidant defense system in SD rats fed a high cholesterol diet. Lab Anim Res 2020; 35:13. [PMID: 32257901 PMCID: PMC7081576 DOI: 10.1186/s42826-019-0013-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/24/2019] [Indexed: 12/19/2022] Open
Abstract
A total of 24 SD rats were allotted to four treatment groups such as the control (CON), 1% of cholesterol diet (CHO), 0.5% of coenzyme Q10 (COQ) and 1% of cholesterol plus 0.5% of coenzyme Q10 (CHCQ) groups to determine the effects of coenzyme Q10 (CoQ10) on the antioxidant defense system in rats. The body weight, weight gain, liver weight and abdominal fat pads were unaffected by 0.5% of CoQ10 supplement in the rats. The level of triglyceride and HDL-cholesterol levels in the blood was significantly increased (p < 0.05) by the 1% of cholesterol supplement (CHO), whereas 0.5% of CoQ10 supplement (COQ) did not alter these blood lipid indices. In the mRNA expression, there was a significant effect (P < 0.05) of the CoQ10 supplement on the mRNA expression of superoxide dismutase (SOD), although the mRNA expression of glutathione peroxidase (GPX) and glutathione S-transferase (GST) was unaffected by cholesterol or the CoQ10 supplement. Similar to mRNA expression of SOD, its activity was also significantly increased (P < 0.05) by CoQ10, but not by the cholesterol supplement effect. The activities hepatic GPX and GST were unaffected by CoQ10 and cholesterol supplements in rats. Lipid peroxidation in the CHO group resulted in a significant (p < 0.05) increase compared with that in the other groups, indicating that the CoQ10 supplement to 1% of cholesterol-fed rats alleviated the production of lipid peroxidation in the liver. In conclusion, 0.5% of the CoQ10 supplement resulted in positive effects on the hepatic antioxidant defense system without affecting blood lipid indices in 1% of cholesterol fed rats.
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Affiliation(s)
- Ha-Na Kim
- 1Department of Animal Science and Biotechnology, and the Regional Animal Research Center, Gyeongnam National University of Science and Technology, Chilam-Dong 150, Jinju, Gyeongnam 52725 Korea
| | - Dong-Gyung Jeon
- 1Department of Animal Science and Biotechnology, and the Regional Animal Research Center, Gyeongnam National University of Science and Technology, Chilam-Dong 150, Jinju, Gyeongnam 52725 Korea
| | - Yong Lim
- 2Department of Clinical Laboratory Science, Dong-Eui Univerisity, Busan, 47340 Korea
| | - In-Surk Jang
- 1Department of Animal Science and Biotechnology, and the Regional Animal Research Center, Gyeongnam National University of Science and Technology, Chilam-Dong 150, Jinju, Gyeongnam 52725 Korea
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37
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Kurotaki Y, Sakai N, Miyazaki T, Hosonuma M, Sato Y, Karakawa A, Chatani M, Myers M, Suzawa T, Negishi-Koga T, Kamijo R, Miyazaki A, Maruoka Y, Takami M. Effects of lipid metabolism on mouse incisor dentinogenesis. Sci Rep 2020; 10:5102. [PMID: 32198436 PMCID: PMC7083963 DOI: 10.1038/s41598-020-61978-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/03/2020] [Indexed: 01/09/2023] Open
Abstract
Tooth formation can be affected by various factors, such as oral disease, drug administration, and systemic illness, as well as internal conditions including dentin formation. Dyslipidemia is an important lifestyle disease, though the relationship of aberrant lipid metabolism with tooth formation has not been clarified. This study was performed to examine the effects of dyslipidemia on tooth formation and tooth development. Dyslipidemia was induced in mice by giving a high-fat diet (HFD) for 12 weeks. Additionally, LDL receptor-deficient (Ldlr−/−) strain mice were used to analyze the effects of dyslipidemia and lipid metabolism in greater detail. In the HFD-fed mice, incisor elongation was decreased and pulp was significantly narrowed, while histological findings revealed disappearance of predentin. In Ldlr−/− mice fed regular chow, incisor elongation showed a decreasing trend and pulp a narrowing trend, while predentin changes were unclear. Serum lipid levels were increased in the HFD-fed wild-type (WT) mice, while Ldlr−/− mice given the HFD showed the greatest increase. These results show important effects of lipid metabolism, especially via the LDL receptor, on tooth homeostasis maintenance. In addition, they suggest a different mechanism for WT and Ldlr−/− mice, though the LDL receptor pathway may not be the only factor involved.
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Affiliation(s)
- Yutaro Kurotaki
- Division of Community-Based Comprehensive Dentistry, Department of Special Needs Dentistry, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan.,Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Nobuhiro Sakai
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan. .,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.
| | - Takuro Miyazaki
- Department of Biochemistry, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Masahiro Hosonuma
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Division of Rheumatology, Department of Medicine, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Yurie Sato
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Division of Dentistry for Persons with Disabilities, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan
| | - Akiko Karakawa
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Masahiro Chatani
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Mie Myers
- Division of Community-Based Comprehensive Dentistry, Department of Special Needs Dentistry, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan
| | - Tetsuo Suzawa
- Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Takako Negishi-Koga
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.,Division of Mucosal Barriology, International Research and Development Center for Mucosal vaccines, The Institute of Medical Science, The Institute of Medical Science The University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan
| | - Ryutaro Kamijo
- Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Akira Miyazaki
- Department of Biochemistry, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Yasubumi Maruoka
- Division of Community-Based Comprehensive Dentistry, Department of Special Needs Dentistry, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan
| | - Masamichi Takami
- Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan. .,Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.
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38
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Wah-Suarez MI, Danford CJ, Patwardhan VR, Jiang ZG, Bonder A. Hyperlipidaemia in primary biliary cholangitis: treatment, safety and efficacy. Frontline Gastroenterol 2019; 10:401-408. [PMID: 31656566 PMCID: PMC6788128 DOI: 10.1136/flgastro-2018-101124] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/04/2018] [Accepted: 12/09/2018] [Indexed: 02/04/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease associated with altered lipoprotein metabolism, mainly cholesterol. Hypercholesterolaemia, a major modifiable risk factor for cardiovascular disease in the general population, occurs in 75%-95% of individuals with PBC. The impact of hypercholesterolaemia on cardiovascular risk in PBC, however, is controversial. Previous data have shown that hypercholesterolaemia in PBC is not always associated with an increase in cardiovascular events. However, patients with PBC with cardiovascular risk factors may still warrant cholesterol-lowering therapy. Treatment of hypercholesterolaemia in PBC poses unique challenges among primary care providers due to concerns of hepatotoxicity associated with cholesterol-lowering medications. This review summarises the current understanding of the pathophysiology of hypercholesterolaemia in PBC and its pertinent cardiovascular risk. We will also discuss indications for treatment and the efficacy and safety of available agents for hypercholesterolaemia in PBC.
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Affiliation(s)
- Martin I Wah-Suarez
- Department of Internal Medicine, University Hospital ’Dr. José Eleuterio González', Monterrey, Mexico
| | - Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Vilas R Patwardhan
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Z Gordon Jiang
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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39
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Kattah L, Gómez A, Gutiérrez S, Puerto K, Moreno-Pallares ED, Jaramillo A, Mendivil CO. Hypercholesterolemia Due to Lipoprotein X: Case Report and Thematic Review. Clin Med Insights Endocrinol Diabetes 2019; 12:1179551419878687. [PMID: 31632171 PMCID: PMC6769215 DOI: 10.1177/1179551419878687] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 08/28/2019] [Indexed: 12/15/2022] Open
Abstract
The liver is a key organ in lipid and lipoprotein metabolism, hence hepatic diseases often manifest as lipid disturbances. Cholestatic liver diseases are frequently associated with an important increase in total cholesterol at the expense of lipoprotein X (LpX), an abnormal lipoprotein isolated and characterized in the 1960s to 1970s in patients with obstructive jaundice. Lipoprotein X is rich in phospholipids, albumin, and free cholesterol, has a density similar to low-density lipoprotein (LDL), and a size similar to very low-density lipoprotein (VLDL), which has hampered its detection through routine laboratory tests. Unlike LDL, LpX has no apoB-100, so it is not removed from circulation via the LDL receptor, and it is not clear whether or not it can be atherogenic. Although LpX was initially described in patients with cholestasis, it has also been found in patients with genetic deficiency of lecithin-cholesterol acyltransferase (LCAT), in patients who receive lipid-rich parenteral nutrition and most recently in patients with graft versus host disease of the liver. In the presence of LpX, plasma total cholesterol can rise up to 1000 mg/dL, which may lead to the development of skin xanthomas and hyperviscosity syndrome. Treatment of LpX-dependent hypercholesterolemia with conventional hypolipidemic drugs is frequently ineffective, and definitive treatment relies on correction of the underlying cause of cholestasis. Here, we present the case of a patient with LpX-dependent hypercholesterolemia in the context of primary biliary cholangitis.
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Affiliation(s)
- Laura Kattah
- Endocrinology Section, Fundación Santa Fe de Bogotá, Bogotá, Colombia
| | - Andrés Gómez
- Division of Gastroenterology, Fundación Santa Fe de Bogotá, Bogotá, Colombia
| | | | | | | | - Andrés Jaramillo
- Endocrinology Section, Fundación Santa Fe de Bogotá, Bogotá, Colombia
| | - Carlos O Mendivil
- Endocrinology Section, Fundación Santa Fe de Bogotá, Bogotá, Colombia
- School of Medicine, Universidad de los Andes, Bogotá, Colombia
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40
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Nascimbeni F, Pellegrini E, Lugari S, Mondelli A, Bursi S, Onfiani G, Carubbi F, Lonardo A. Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes. Atherosclerosis 2019; 284:66-74. [PMID: 30875495 DOI: 10.1016/j.atherosclerosis.2019.02.028] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of alcohol-like hepatic histological changes, which occur in the absence of any competing causes of chronic liver disease, notably including significant alcohol consumption. A close and bi-directional relationship links NAFLD with the metabolic syndrome (MetS), and concurrent MetS will hasten the progression to more severe forms of NAFLD, including cirrhosis and hepatocellular carcinoma (HCC). Patients with NAFLD will typically exhibit atherogenic dyslipidemia and increased cardiovascular risk (CVR). Statins are among the most widely prescribed lipid-lowering drugs. Their use has historically been hampered, in individuals with liver disease, owing to the fear of hepatotoxicity. However, studies suggest that statins are not only effective in reducing cardiovascular events, but may also exert multiple beneficial effects on the liver. CVR in those with NAFLD has extensively been covered by our group and others. This updated clinical narrative review will critically examine the effects of statins on the pathogenesis of NAFLD, including the key elementary pathological lesions of NAFLD, i.e. steatosis, inflammation and fibrosis, and its liver-related complications, i.e. cirrhosis, portal hypertension and HCC.
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Affiliation(s)
- Fabio Nascimbeni
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy.
| | - Elisa Pellegrini
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Simonetta Lugari
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Alberto Mondelli
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Serena Bursi
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Giovanna Onfiani
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Francesca Carubbi
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Amedeo Lonardo
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
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Yu M, Pan L, Sang C, Mu Q, Zheng L, Luo G, Xu N. Apolipoprotein M could inhibit growth and metastasis of SMMC7721 cells via vitamin D receptor signaling. Cancer Manag Res 2019; 11:3691-3701. [PMID: 31190977 PMCID: PMC6525829 DOI: 10.2147/cmar.s202799] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality-to-incidence ratios. Apolipoprotein M (ApoM), a member of the apolipoprotein family, is mainly synthesized in the liver, whereas its role in HCC has not been elucidated. Here, we examined the effect of ApoM on the biological behavior of HCC cells and the possible mechanisms. Methods: We used CRISPR/Cas9 technology to knock out ApoM in SMMC7721 cells. Differentially expressed genes before and after ApoM knockout (KO) were analyzed by GeneChip microarrays and confirmed by qRT-PCR. Cell assays of proliferation, apoptosis, migration and invasion were performed in SMMC7721 cells, and the expression of epithelial-mesenchymal transition (EMT) markers was performed by western blot. And we performed functional recovery experiments by overexpressing vitamin D receptor (VDR) in SMMC7721. Results: The ApoM-KO SMMC7721 cell line was successfully constructed using the CRISPR/Cas9 technology. Our results showed that silencing ApoM suppressed apoptosis and promoted proliferation, migration, invasion and EMT of SMMC7721 cells. The microarray data revealed that a total of 1,868 differentially expressed genes were identified, including VDR. The qRT-PCR and western blot verification results demonstrated that knocking out ApoM could significantly reduce the expression of VDR. The functional recovery experiments indicated that VDR overexpression could offset the inhibition of cell apoptosis and the promotion of cell proliferation, migration, invasion and EMT caused by knocking out ApoM in SMMC7721 cells. Conclusion: ApoM could function as a tumor suppressor to inhibit the growth and metastasis of SMMC7721 cells via VDR signaling in HCC.
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Affiliation(s)
- Miaomei Yu
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Lili Pan
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Chen Sang
- Department of Cardiothoracic Surgery, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Qinfeng Mu
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Lu Zheng
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Guanghua Luo
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou213003, People’s Republic of China
| | - Ning Xu
- Section of Clinical Chemistry and Pharmacology, Institute of Laboratory Medicine, Lunds University, LundS‑22185, Sweden
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Abstract
PURPOSE OF REVIEW Lipoprotein-X (Lp-X) is an abnormal lipoprotein containing abundant free cholesterol and phospholipids, as well as some apolipoprotein E (apoE). Serum Lp-X increases in patients with cholestasis and lecithin-cholesterol acyltransferase deficiency, as well as in those receiving intravenous lipid emulsion. Lp-X is often associated with skin xanthomas in cholestatic patients. However, earlier studies showed that Lp-X is not taken up by murine macrophages, but exerts antiatherogenic actions. In this review, we discuss the heterogeneity of Lp-X and its potential atherogenicity. RECENT FINDINGS Mass spectrometry revealed that Lp-X of cholestatic patients is similar in lipid composition to low-density lipoprotein (LDL) and high-density lipoprotein, but not to bile acids, suggesting that Lp-X is synthesized in the liver. Palmar xanthomas appear in patients with cholestasis, but regress over months after improvement of hypercholesterolemia. Lp-X isolated from cholestatic patients is rich in apoE, and causes more lipid accumulation than oxidized LDL and acetyl LDL in human monocyte-derived macrophages. SUMMARY Lp-X is heterogeneous in apoE content. Lp-X is taken up in cholestatic patients by apoE-recognizing lipoprotein receptors. Further research is warranted to fully understand the atherogenicity of Lp-X and the clinical significance of elevated Lp-X concentrations, particularly in cholestatic patients.
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Affiliation(s)
- Takashi Miida
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Galas M, Glówczyńska R, Lewandowski Z, Cacko A, Raszeja-Wyszomirska J, Milkiewicz P, Krawczyk M, Zieniewicz K, Opolski G. Etiology of Liver Disease and Cardiovascular Abnormalities in Patients on a Liver Transplantation Waiting List. Ann Transplant 2019; 24:162-167. [PMID: 30898994 PMCID: PMC6442494 DOI: 10.12659/aot.913061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The classical cardiovascular risk factors and changes in the circulatory system secondary to end-stage liver disease (ESLD) are associated with an increased risk of cardiac abnormalities (CAs) in patients waiting for liver transplantation (LTx). The aim of this study was to assess the relationship between the etiology of liver disease and the presence of CAs in patients qualified for LTx. MATERIAL AND METHODS The study enrolled patients qualified to LTx due to ESLD at the Clinical Hospital of the Medical University of Warsaw between 2013 and 2016. Out of 396 patients: 65, 157, 117, and 57 had ESLD due to the alcoholic liver disease (ALD), viral infections (VIR), autoimmune disorders (AUTO), and different etiologies (OTHER), respectively. RESULTS An increased frequency of hypertension and diabetes mellitus were observed in ALD and VIR groups, while for hyperlipidemia, the highest rates were observed in ALD and AUTO groups. Significant differences in CAs rates were observed for resting tachycardia, prolonged QT interval, bradycardia, and left ventricular diastolic dysfunction. After adjustment for age, MELD, and Child-Pugh scores, hyperlipidemia (26% vs. 7-15%, p<0.048) was most frequently observed in the AUTO group, while poor aerobic capacity (49% vs. 21-34%, p<0.009) dominated in the OTHER group. CONCLUSIONS The frequency of hyperlipidemia, and poor aerobic capacity were directly related to the etiology of liver disease, while the remaining associations resulted from effects of age, MELD, and Child-Pugh score.
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Affiliation(s)
- Michalina Galas
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Renata Glówczyńska
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Zbigniew Lewandowski
- Department of Epidemiology and Biostatistics, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Cacko
- Department of Medical Informatics and Telemedicine, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Raszeja-Wyszomirska
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Grzegorz Opolski
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
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Extreme hypercholesterolemia in cholestatic sarcoidosis due to lipoprotein X: Exploring the cholesterol gap. JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY CASE REPORTS 2018. [DOI: 10.1016/j.jecr.2018.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Zamanian Z, Yousefinejad S, Khoshnoud MJ, Golbabaie F, Farhang Dehghan S, Modaresi A, Amanat S, Reza Zare M, Rahmani A. Toxic effects of subacute inhalation exposure to trichloroethylene on serum lipid profile, glucose and biochemical parameters in Sprague-Dawley rats. Inhal Toxicol 2018; 30:354-360. [PMID: 30479189 DOI: 10.1080/08958378.2018.1526233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The current study evaluated the inhalation toxicity of trichloroethylene (TCE) at 0, 10, 100, 250 and 400 ppm in Sprague-Dawley rats for 10 day period, because the subacute inhalation toxicity of TCE on serum lipid profile, glucose and some biochemical parameters has not been previously reported. TCE vapors were generated using the dynamic generation system based on evaporation method in the exposure chamber. On the basis of the results, mean serum low-density lipoprotein (LDL) and albumin (ALB) decreased significantly in all the groups exposed to TCE compared with the control group (p < .005), but there was a significant increase for parameters: fasting blood glucose (FBG) and alkaline phosphatase (ALP) (p < .005). Rats exposed to 400 ppm TCE showed a significant decrease in serum cholesterol (CHOL) and protein (Pr) compared with the control group (p < .005). A negative relationship was found between triglycerides (TG), very low density lipoprotein (VLDL), CHOL, LDL, Pr, ALB and urea levels and the subacute exposure to concentrations of TCE (R2 = -0.26, p < .05), but there was a direct correlation for parameters FBG, ALP and alanine aminotransferase (ALT) (R2 = 0.42, p < .05). In conclusion, studies with Sprague-Dawley rats demonstrated that subacute inhalation exposure to TCE (≥ 100 PPM) is associated with biochemical and lipotoxicity in the form of decreased serum ALB and LDL and raised ALP and glucose levels. The present study also provides additional evidence relating to decreased serum CHOL and Pr after subacute inhalation exposure to 400 ppm TCE.
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Affiliation(s)
- Zahra Zamanian
- a Department of Occupational Health Engineering, School of Health , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Saeed Yousefinejad
- a Department of Occupational Health Engineering, School of Health , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammad Javad Khoshnoud
- b Department of Pharmacology Toxicology, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Farideh Golbabaie
- c Department of Occupational Health, School of Public Health , Tehran University of Medical Sciences , Tehran , Iran
| | - Somayeh Farhang Dehghan
- d Department of Occupational Health, School of Public Health and Safety , Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Aboutaleb Modaresi
- e Modaresi Laboratory , Larestan University of Medical Sciences, Larestan , Iran
| | - Sasan Amanat
- f Department of Nutrition, School of Public Health , Larestan University of Medical Sciences , Larestan , Iran
| | - Mohammad Reza Zare
- g Department of Environmental Health Engineering, School of Health , Larestan University of Medical Sciences , Larestan , Iran
| | - Abdolrasoul Rahmani
- a Department of Occupational Health Engineering, School of Health , Shiraz University of Medical Sciences , Shiraz , Iran
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Benito-Vicente A, Uribe KB, Jebari S, Galicia-Garcia U, Ostolaza H, Martin C. Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. Int J Mol Sci 2018; 19:ijms19113426. [PMID: 30388787 PMCID: PMC6275065 DOI: 10.3390/ijms19113426] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 10/21/2018] [Accepted: 10/29/2018] [Indexed: 12/18/2022] Open
Abstract
Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Once acquired, both are delivered to peripheral tissues in a lipoprotein dependent mechanism. Malfunctioning of cholesterol metabolism is caused by multiple hereditary diseases, including Familial Hypercholesterolemia, Sitosterolemia Type C and Niemann-Pick Type C1. Of these, familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder characterized by high plasma cholesterol levels. Its frequency is estimated to be 1:200 and, if untreated, increases the risk of premature cardiovascular disease. This review aims to summarize the current knowledge on cholesterol metabolism and the relation of FH to cholesterol homeostasis with special focus on the genetics, diagnosis and treatment.
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Affiliation(s)
- Asier Benito-Vicente
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
| | - Kepa B Uribe
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
| | - Shifa Jebari
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
| | - Unai Galicia-Garcia
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
| | - Helena Ostolaza
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
| | - Cesar Martin
- Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.
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Geng C, Dong T, Jin W, Yu B, Yin F, Peng F, Chen G, Ji C, Ding F. MicroRNA-98 regulates hepatic cholesterol metabolism via targeting sterol regulatory element-binding protein 2. Biochem Biophys Res Commun 2018; 504:422-426. [DOI: 10.1016/j.bbrc.2018.08.205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/31/2018] [Indexed: 11/24/2022]
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Xie W, Wang Q, Gao Y, Pan CQ. Vanishing bile duct syndrome with hyperlipidemia after ibuprofen therapy in an adult patient: a case report. BMC Gastroenterol 2018; 18:142. [PMID: 30268094 PMCID: PMC6162916 DOI: 10.1186/s12876-018-0869-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 09/06/2018] [Indexed: 12/15/2022] Open
Abstract
Background Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause drug-induced liver injury. Although patients with drug-induced liver injury from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Recently, a few cases of children with persistent jaundice reported have been linked to the vanishing bile duct syndrome. However, data on adult patients is limited. Case presentation We report herein a case of an adult patient who had persistent cholestasis with hyperlipidemia from the VBDS after ibuprofen use. We described a female patient with severe jaundice after taking ibuprofen, although she had no history of liver disease before. The drug-induced liver injury from ibuprofen was identified by clinical features and liver biopsy, which included the Roussel Uclaf Causality Assessment Method scores of 6 and pathological features of cholestasis with stage four drug-induced injury as well as loss of bile duct structures. The clinical course was featuring with persistently high levels of bilirubin associated with hyperlipidemia over the period of one month, although the laboratory abnormalities were slightly improved spontaneously after the cessation of ibuprofen. Her autoantibodies markers including AMA-M2 ASMA, RO-52, LKM, SLA, and anti-glycoprotein-210 were negative. The second liver biopsy was performed on day 213 due to persistent hyperbilirubinemia. Pathological findings were consistent with the diagnosis of vanishing bile duct syndrome. Conclusions A rare case of ibuprofen-associated vanishing bile duct syndrome in an adult female patient is presented. Clinicians need to be aware of vanishing bile duct syndrome as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.
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Affiliation(s)
- Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Calvin Q Pan
- Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University School of Medicine, 132-21 41Ave, Flushing, New York, 11355, USA.
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Ying F, Cai Y, Wong HK, Chen XY, Huang IB, Vanhoutte PM, Xia Z, Xu A, Tang EHC. EP4 emerges as a novel regulator of bile acid synthesis and its activation protects against hypercholesterolemia. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1029-1040. [DOI: 10.1016/j.bbalip.2018.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/16/2018] [Accepted: 06/03/2018] [Indexed: 12/17/2022]
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Karnik S, Lee C, Cancino A, Bhushan A. Real-time measurement of cholesterol secreted by human hepatocytes using a novel microfluidic assay. TECHNOLOGY 2018; 6:135-141. [PMID: 31548979 PMCID: PMC6756770 DOI: 10.1142/s2339547818500097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The use of microfluidics has become widespread in recent years because of the use of lesser resources such as small size, low volume of reagents, and physiological representation of mammalian cells. One of the advantages of microfluidic-based cell culture is the ability to perfuse culture media which tends to improve cellular health and function. Although measurement of cellular function conventionally is carried out using well-plates and plate readers, these approaches are insufficient to carry out in-line analysis of perfused cell cultures because of mismatch between volumes and sensitivity. We report the development of a novel microfluidic device and assay that is carried out under perfusion, in-line to measure the cholesterol secreted from a human hepatocyte tissue-chip. The heart of the assay is the unique implementation of enzymatic chemistry that is carried out on a polystyrene bead. Using this approach, we successfully measured cholesterol secreted by the perfused human hepatocytes.
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Affiliation(s)
- Sonali Karnik
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
| | - Chaeeun Lee
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
| | - Andrea Cancino
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
| | - Abhinav Bhushan
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
- Corresponding Author: Abhinav Bhushan, Assistant Professor, Department of Biomedical Engineering, Illinois Institute of Technology, Chicago,
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