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1
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Schönberg J, Borlak J. miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures. Mol Cell Biochem 2025; 480:2573-2593. [PMID: 39424772 PMCID: PMC11961548 DOI: 10.1007/s11010-024-05129-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/29/2024] [Indexed: 10/21/2024]
Abstract
Primary non-function (PNF) of an allograft defines an irreversible graft failure and although rare, constitutes a life-threatening condition that requires high-urgency re-transplantation. Equally, drug induced acute liver failures (ALF) are seldom but the rapid loss of hepatic function may require orthotropic liver transplantation (OLT). Recently, we reported the development of a rodent PNF-disease model of fatty allografts and showed that a dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of PNF. Based on findings from the rat PNF-disease model, we selected 15 miRNA-biomarker candidates for clinical validation and performed RT-qPCRs in well-documented PNF cases following OLT of fatty allografts. To assess specificity and selectivity, we compared their regulation in pre- and intraoperative liver biopsies and pre- and post-operative blood samples of patients undergoing elective hepatobiliary surgery. Additionally, we assessed their regulation in drug induced ALF. We confirmed clinical relevance for 11 PNF-associated miRNAs and found expression of miRNA-27b-3p, miRNA-122-3p, miRNA-125a-5p, miRNA-125b-5p and miRNA-192-5p to correlate with the hepatic steatosis grades. Furthermore, we demonstrate selectivity and specificity for the biomarker candidates with opposite regulation of let-7b-5p, miRNA-122-5p, miRNA-125b-5p and miRNA-194-5p in blood samples of patients following successful OLTs and/or liver resection. Moreover, by considering findings from 21 independent ALF-studies, we observed nine PNF-associated miRNAs regulated in common. We report miRNAs highly regulated in PNF and ALF, and their common regulation in different diseases broadens the perspective as biomarker candidates. Our study warrants independent confirmation in randomized clinical trials.
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Affiliation(s)
- Juliette Schönberg
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
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2
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Amatya R, Joseph A, Roh GS, Moon C, Benmokadem Y, Kim D, Min KA, Shin MC. Combined Esculentin-2CHa Fusion Protein-Coated Au Nanoparticles for Effective Against Non-Alcoholic Fatty Liver Disease in Mice Model. Int J Nanomedicine 2025; 20:3407-3421. [PMID: 40125429 PMCID: PMC11928441 DOI: 10.2147/ijn.s497645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction Extensive research has focused on identifying effective treatments for NAFLD, with numerous bioactive peptide candidates showing significant promise. In this research, a long-acting esculentin-2CHa(1-30)-coated AuNPs (ESC-ABD-AuNPs) was developed and the applicability was evaluated for their use in the treatment of non-alcoholic fatty liver disease (NAFLD). Methods ESC-ABD-AuNPs were synthesized by adopting a 1-step reduction process and the successful preparation of the nanoparticles (NPs) was assessed by various physical characterizations including transmission electron microscopy (TEM), ultraviolet-visible (UV-VIS) absorption spectra, dynamic light scattering (DLS), and Fourier Transform Infrared Spectroscopy (FT-IR). After the ESC-ABD-AuNPs were prepared, cytotoxicity, pharmacokinetics (PK), and biodistribution profiles were identified. Then, with a high-fat diet (HFD)-fed obese mice model, efficacy studies were carried out focused on their effects for anti-hyperglycemia and anti-NAFLD. Furthermore, the feasibility of loading a small molecule onto the NPs was evaluated for potential combination therapy. Results ESC-ABD-AuNPs were synthesized with an average hydrodynamic size of 120 (±10) nm and demonstrated good stability and an extended plasma half-life of 28.3 h. The NPs exhibited high liver accumulation and were well tolerated in cell viability tests. In PK and biodistribution studies, ESC-ABD-AuNPs showed prolonged retention in major organs, such as the pancreas and the liver. Therapeutic efficacy was demonstrated in the HFD-fed obese mice, where the ESC-ABD-AuNPs significantly reduced blood glucose levels, improved glucose tolerance, and mitigated liver fat accumulation. The ESC-ABD-AuNPs platform also showed potential for combination therapies, demonstrated by its ability to load obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, found effective for the treatment of NAFLD in clinical studies. Conclusion Overall, this study has demonstrated the promising potential of ESC-ABD-AuNPs as a novel treatment for NAFLD. This research suggests that ESC-ABD-AuNPs could be a significant advancement in drug delivery and liver disease treatment, particularly for combination therapies.
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Affiliation(s)
- Reeju Amatya
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Amala Joseph
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam, 52727, Republic of Korea
| | - Cheol Moon
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Jeonnam, 57922, Republic of Korea
| | - Yassmine Benmokadem
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Doyeon Kim
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Kyoung Ah Min
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
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3
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Smith K, Dennis KMJH, Hodson L. The ins and outs of liver fat metabolism: The effect of phenotype and diet on risk of intrahepatic triglyceride accumulation. Exp Physiol 2025. [PMID: 39861959 DOI: 10.1113/ep092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/22/2024] [Indexed: 01/27/2025]
Abstract
In health, the liver is a metabolically flexible organ that plays a key role in regulating systemic lipid and glucose concentrations. There is a constant flux of fatty acids (FAs) to the liver from multiple sources, including adipose tissue, dietary, endogenously synthesized from non-lipid precursors, intrahepatic lipid droplets and recycling of triglyceride-rich remnants. Within the liver, FAs are used for triglyceride synthesis, which can be oxidized, stored or secreted in very low-density lipoproteins into the systemic circulation. The processes of FA uptake, FA synthesis and the intracellular partitioning of FAs into storage, oxidation or secretory pathways are tightly regulated. An imbalance in these processes causes intrahepatic triglyceride to accumulate and is associated with the development of metabolic dysfunction-associated steatotic liver disease. It is well appreciated that many factors can influence intrahepatic FA partitioning, and although there is good evidence that both phenotype (e.g., sex, ethnicity and adiposity) and dietary macronutrient composition can play a role in intrahepatic triglyceride accumulation, their interaction remains poorly understood. The aim of this review is to explore how the respective pathways of FA delivery, synthesis and disposal are altered by phenotype and understand how dietary macronutrient composition might influence the partitioning of FAs in the liver in vivo, in humans.
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Affiliation(s)
- Kieran Smith
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Kaitlyn M J H Dennis
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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4
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Tang S, Borlak J. Genomics of human NAFLD: Lack of data reproducibility and high interpatient variability in drug target expression as major causes of drug failures. Hepatology 2024; 80:901-915. [PMID: 38358517 PMCID: PMC11407777 DOI: 10.1097/hep.0000000000000780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND AND AIMS NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail. To better comprehend drug failures, we investigated the reproducibility of fatty liver genomic data across 418 liver biopsies and evaluated the interpatient variability of 18 drug targets. APPROACH AND RESULTS Apart from our own data, we retrieved NAFLD biopsy genomic data sets from public repositories and considered patient demographics. We divided the data into test and validation sets, assessed the reproducibility of differentially expressed genes and performed gene enrichment analysis. Patients were stratified by disease activity score, fibrosis grades and sex, and we investigated the regulation of 18 drug targets across 418 NAFLD biopsies of which 278 are NASH cases. We observed poor reproducibility of differentially expressed genes across 9 independent studies. On average, only 4% of differentially expressed genes are commonly regulated based on identical sex and 2% based on identical NAS disease score and fibrosis grade. Furthermore, we observed sex-specific gene regulations, and for females, we noticed induced expression of genes coding for inflammatory response, Ag presentation, and processing. Conversely, extracellular matrix receptor interactions are upregulated in males, and the data agree with clinical findings. Strikingly, and with the exception of stearoyl-CoA desaturase, most drug targets are not regulated in > 80% of patients. CONCLUSIONS Lack of data reproducibility, high interpatient variability, and the absence of disease-dependent drug target regulations are likely causes of NASH drug failures in clinical trials.
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Wang J, Li H, Wang X, Shi R, Hu J, Zeng X, Luo H, Yang P, Luo H, Cao Y, Cai X, Chen S, Wang D. Association between triglyceride to high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease and liver fibrosis in American adults: an observational study from the National Health and Nutrition Examination Survey 2017-2020. Front Endocrinol (Lausanne) 2024; 15:1362396. [PMID: 39081791 PMCID: PMC11286417 DOI: 10.3389/fendo.2024.1362396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 07/03/2024] [Indexed: 08/02/2024] Open
Abstract
Objective This study investigated the link between triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and nonalcoholic fatty liver disease (NAFLD) and liver fibrosis in American adults. Methods Information for 6495 participants from the National Health and Nutrition Examination Survey (NHANES) 2017-2020.03 was used for this cross-sectional study. The link between TG/HDL-C ratios and NAFLD and liver fibrosis was assessed by multiple linear regression before evaluating nonlinear correlations based on smoothed curve fitting models. Stratification analysis was then applied to confirm whether the dependent and independent variables displayed a stable association across populations. Results TG/HDL-C ratios were positively correlated with NAFLD, with higher ratios being linked to increased prevalence of NAFLD. After adjusting for potential confounders, the odds ratios (OR) for NAFLD patients in the fourth TG/HDL-C quartile were 3.61 (95% confidence interval [CI], 2.94-4.38) (P for trend < 0.001) in comparison with those in the first quartile after adjusting for clinical variables. However, no statistical significance was noted for the ratio for liver fibrosis after adjusting for potential confounders (P for trend = 0.07). A nonlinear correlation between TG/HDL-C ratios and NAFLD was observed based on smoothed curve fitting models. However, a nonlinear relationship between the ratios and liver fibrosis was not established. In subgroup analyses, there was an interaction between smoking status and TG/HDL-C ratio in relation to the prevalence of liver fibrosis (P for interaction < 0.001). Conclusions Among American adults, the TG/HDL-C ratio was noted to be nonlinearly positively associated with the prevalence of NAFLD; however, this relationship was not present in liver fibrosis.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Han Li
- Department of Cardiology, The Fifth Hospital of Wuhan, Wuhan, China
| | - Xiaoyi Wang
- Department of Neurosurgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Junchao Hu
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hua Luo
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Pei Yang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Cao
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xianfu Cai
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Sirui Chen
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Decai Wang
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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Rudolph EL, Chin L. Mechanobiology in Metabolic Dysfunction-Associated Steatotic Liver Disease and Obesity. Curr Issues Mol Biol 2024; 46:7134-7146. [PMID: 39057066 PMCID: PMC11276231 DOI: 10.3390/cimb46070425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/30/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
With the ongoing obesity epidemic, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to rise and necessitates a greater understanding of how the disease proceeds from benign excess lipid in hepatocytes to liver fibrosis and eventually to liver cancer. MASLD is caused, at least in part, by hepatocytes' storage of free fatty acids (FAs) that dysfunctional adipocytes are no longer able to store, and therefore, MASLD is a disease that involves both the liver and adipose tissues. The disease progression is not only facilitated by biochemical signals, but also by mechanical cues such as the increase in stiffness often seen with fibrotic fatty livers. The change in stiffness and accumulation of excess lipid droplets impact the ability of a cell to mechanosense and mechanotranduce, which perpetuates the disease. A mechanosensitive protein that is largely unexplored and could serve as a potential therapeutic target is the intermediate filament vimentin. In this review, we briefly summarize the recent research on hepatocyte and adipocyte mechanobiology and provide a synopsis of studies on the varied, and sometimes contradictory, roles of vimentin. This review is intended to benefit and encourage future studies on hepatocyte and adipocyte mechanobiology in the context of MASLD and obesity.
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Affiliation(s)
| | - LiKang Chin
- Department of Biomedical Engineering, Widener University, Chester, PA 19013, USA;
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7
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Ho PY, Chou YC, Koh YC, Lin WS, Chen WJ, Tseng AL, Gung CL, Wei YS, Pan MH. Lactobacillus rhamnosus 069 and Lactobacillus brevis 031: Unraveling Strain-Specific Pathways for Modulating Lipid Metabolism and Attenuating High-Fat-Diet-Induced Obesity in Mice. ACS OMEGA 2024; 9:28520-28533. [PMID: 38973907 PMCID: PMC11223209 DOI: 10.1021/acsomega.4c02514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/29/2024] [Accepted: 05/09/2024] [Indexed: 07/09/2024]
Abstract
Obesity is a global health crisis, marked by excessive fat in tissues that function as immune organs, linked to microbiota dysregulation and adipose inflammation. Investigating the effects of Lactobacillus rhamnosus SG069 (LR069) and Lactobacillus brevis SG031 (LB031) on obesity and lipid metabolism, this research highlights adipose tissue's critical immune-metabolic role and the probiotics' potential against diet-induced obesity. Mice fed a high-fat diet were treated with either LR069 or LB031 for 12 weeks. Administration of LB031 boosted lipid metabolism, indicated by higher AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, and increased the M2/M1 macrophage ratio, indicating LB031's anti-inflammatory effect. Meanwhile, LR069 administration not only led to significant weight loss by enhancing lipolysis which evidenced by increased phosphorylation of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) but also elevated Akkermansia and fecal acetic acid levels, showing the gut microbiota's pivotal role in its antiobesity effects. LR069 and LB031 exhibit distinct effects on lipid metabolism and obesity, underscoring their potential for precise interventions. This research elucidates the unique impacts of these strains on metabolic health and highlights the intricate relationship between gut microbiota and obesity, advancing our knowledge of probiotics' therapeutic potential.
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Affiliation(s)
- Pin-Yu Ho
- Institute
of Food Science and Technology, National
Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
| | - Ya-Chun Chou
- Institute
of Food Science and Technology, National
Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
| | - Yen-Chun Koh
- Institute
of Food Science and Technology, National
Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
| | - Wei-Sheng Lin
- Institute
of Food Science and Technology, National
Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
- Department
of Food Science, National Quemoy University, Quemoy County 89250, Taiwan, ROC
| | - Wei-Jen Chen
- Syngen
Biotech Co., Ltd., Building
A, No. 154, Kaiyuan Rd., Sinying, Tainan 73055, Taiwan
| | - Ai-Lun Tseng
- Syngen
Biotech Co., Ltd., Building
A, No. 154, Kaiyuan Rd., Sinying, Tainan 73055, Taiwan
| | - Chiau-Ling Gung
- Syngen
Biotech Co., Ltd., Building
A, No. 154, Kaiyuan Rd., Sinying, Tainan 73055, Taiwan
| | - Yu-Shan Wei
- Syngen
Biotech Co., Ltd., Building
A, No. 154, Kaiyuan Rd., Sinying, Tainan 73055, Taiwan
| | - Min-Hsiung Pan
- Institute
of Food Science and Technology, National
Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
- Department
of Public Health, China Medical University, 91, Hsueh-Shih Road, Taichung 40402, Taiwan, ROC
- Department
of Food Nutrition and Health Biotechnology, Asia University, 500,
Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC
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Westcott F, Dearlove DJ, Hodson L. Hepatic fatty acid and glucose handling in metabolic disease: Potential impact on cardiovascular disease risk. Atherosclerosis 2024; 394:117237. [PMID: 37633797 DOI: 10.1016/j.atherosclerosis.2023.117237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/28/2023]
Abstract
The prevalence of metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing. Although invariably associated with obesity, the importance of fat deposition in non-adipose tissue organs has yet to be fully explored. Pathological ectopic fat deposition within the liver (known as (MASLD)) has been suggested to underlie the development of T2DM and is now emerging as an independent risk factor for cardiovascular disease (CVD). The process of hepatic de novo lipogenesis (DNL), that is the synthesis of fatty acids from non-lipid precursors (e.g. glucose), has received much attention as it sits at the intersect of hepatic glucose and fatty acid handling. An upregulation of the DNL pathway has been suggested to be central in the development of metabolic diseases (including MASLD, insulin resistance, and T2DM). Here we review the evidence to determine if hepatic DNL may play a role in the development of MASLD and T2DM and therefore underlie an increased risk of CVD.
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Affiliation(s)
- Felix Westcott
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
| | - David J Dearlove
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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9
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Abbas SH, Ceresa CDL, Hodson L, Nasralla D, Watson CJE, Mergental H, Coussios C, Kaloyirou F, Brusby K, Mora A, Thomas H, Kounali D, Keen K, Pollok JM, Gaurav R, Iype S, Jassem W, Perera MTP, Hakeem AR, Knight S, Friend PJ. Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study. Trials 2024; 25:386. [PMID: 38886851 PMCID: PMC11181618 DOI: 10.1186/s13063-024-08189-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION ISRCTN ISRCTN14957538. Registered in October 2022.
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Affiliation(s)
- Syed Hussain Abbas
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK.
| | - Carlo D L Ceresa
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
| | - David Nasralla
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Christopher J E Watson
- Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK
| | - Hynek Mergental
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK
- TransMedics Inc, 200 Minuteman Road, Andover, MA, 01810, USA
| | - Constantin Coussios
- Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, UK
| | | | | | - Ana Mora
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0BB, UK
| | - Helen Thomas
- NHS Blood and Transplant Clinical Trials Unit, Fox Den Road, Stoke Gifford, Bristol, BS34 8RR, UK
| | - Daphne Kounali
- Oxford Clinical Trials Research Unit (OCTRU), Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Medical Sciences Division, The Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK
| | - Katie Keen
- NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK
| | - Joerg-Matthias Pollok
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Rohit Gaurav
- Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK
| | - Satheesh Iype
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Wayel Jassem
- Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
| | - M Thamara Pr Perera
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK
| | - Abdul Rahman Hakeem
- Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
- St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK
| | - Simon Knight
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
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10
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Xing W, Li S. LncRNA ENSGALG00000021686 regulates fat metabolism in chicken hepatocytes via miR-146b/AGPAT2 pathway. Anim Genet 2024; 55:420-429. [PMID: 38369771 DOI: 10.1111/age.13405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 01/10/2024] [Accepted: 01/31/2024] [Indexed: 02/20/2024]
Abstract
The liver contributes to lipid metabolism as the hub of fat synthesis. Long non-coding RNAs (lncRNAs) are considered the regulators of cellular processes. Since LncRNA ENSGALG00000021686 (lncRNA 21 686) has been described as a regulator of lipid metabolism, the present study aimed to clarify the role of lncRNA 21 686 in chicken hepatocytes' lipid metabolism. Thirty-two chickens were divided into four groups and were treated with diets containing different amounts of fat, and the hepatic expression of lncRNA 21 686 and miR-146b along with the levels of proteins involved in the regulation of fat metabolism, lipid indices and oxidative stress were measured. Moreover, primary chicken hepatocytes were transfected with lncRNA 21 686 small interfering RNA or microRNA (miRNA, miR)-146b mimics to measure the consequences of suppressing lncRNA or inducing miRNA expression on the levels of proteins involved in fat metabolism and stress markers. The results showed that the high-fat diet modulated the expression of lncRNA 21 686 and miR-146b (p-value < 0.001). Moreover, there was a significant increase in 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 (AGPAT2) gene expression and protein levels and modulated fat-related markers. Furthermore, the results showed that lncRNA 21 686 suppression reduced the expression of AGPAT2 and its downstream proteins (p-value < 0.05). Overexpression of miR-146b regulated fat metabolism indicator expression. Transfection experiments revealed that lncRNA 21 686 suppression increased miR-146b expression. The findings suggested a novel mechanism containing lncRNA 21 686/miR-146b/AGPAT2 in the regulation of fat metabolism in chicken hepatocytes.
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Affiliation(s)
- Wenhao Xing
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Shijie Li
- Dongying Jintengsheng Medical Device Sales Co., Ltd., Dongying, Shandong Province, China
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Allard J, Bucher S, Ferron PJ, Launay Y, Fromenty B. Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug-induced liver injury. Fundam Clin Pharmacol 2024; 38:152-167. [PMID: 37665028 DOI: 10.1111/fcp.12951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 07/27/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. OBJECTIVES This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. METHODS Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. RESULTS Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. CONCLUSION While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.
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Affiliation(s)
- Julien Allard
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | | | - Pierre-Jean Ferron
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
| | - Youenn Launay
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
| | - Bernard Fromenty
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
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12
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Kulik U, Moesta C, Spanel R, Borlak J. Dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of primary nonfunction of fatty liver allografts. Transl Res 2024; 264:33-65. [PMID: 37722450 DOI: 10.1016/j.trsl.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 09/20/2023]
Abstract
Orthotopic liver transplantation (OLT) is a lifesaving procedure. However, grafts may fail due to primary nonfunction (PNF). In the past, we demonstrated PNFs to be mainly associated with fatty allografts, and given its unpredictable nature, the development of a disease model is urgently needed. In an effort to investigate mechanism of fatty allograft-associated PNFs, we induced fatty liver disease in donor animals by feeding rats a diet deficient in methionine and choline (MCD). We performed OLT with allografts of different grades of hepatic steatosis and compared the results to healthy ones. We assessed liver function by considering serum biochemistries, and investigated genome wide responses following OLT of healthy and fatty allograft-associated PNFs. Furthermore, we performed immunohistochemistry to evaluate markers of oxidative stress and reperfusion injury, inflammation, glycolysis and gluconeogenesis, lactate transport, and its utilization as part of the Cori cycle. Strikingly, PNFs are strictly lipid content dependent. Nonetheless, a fat content of ≤17% and an increase in the size of hepatocytes of ≤11% (ballooning) greatly improved outcome of OLTs and the hepatic microcirculation. Mechanistically, PNFs arise from a dysfunctional Cori cycle with complete ablation of the lactate transporter SLC16A1. Thus, lipid-laden hepatocytes fail to perform gluconeogenesis via lactate reutilization, and the resultant hyperlactatemia and lactic acidosis causes cardiac arrhythmogenicity and death. Furthermore, the genomic and immunohistochemistry investigations underscore a dysfunctional Krebs cycle with impaired energy metabolism in lipid-burdened mitochondria. Together, we show fatty allografts to be highly vulnerable towards ischemia/reperfusion-injury, and stabilizing the Cori cycle is of critical importance to avert PNFs.
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Affiliation(s)
- Ulf Kulik
- Department of General, Visceral- and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Caroline Moesta
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Reinhard Spanel
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Guo Y, Livelo C, Melkani G. Time-restricted feeding regulates lipid metabolism under metabolic challenges. Bioessays 2023; 45:e2300157. [PMID: 37850554 PMCID: PMC10841423 DOI: 10.1002/bies.202300157] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 10/19/2023]
Abstract
Dysregulation of lipid metabolism is a commonly observed feature associated with metabolic syndrome and leads to the development of negative health outcomes such as obesity, diabetes mellitus, non-alcoholic fatty liver disease, or atherosclerosis. Time-restricted feeding/eating (TRF/TRE), an emerging dietary intervention, has been shown to promote pleiotropic health benefits including the alteration of diurnal expression of genes associated with lipid metabolism, as well as levels of lipid species. Although TRF likely induces a response in multiple organs leading to the modulation of lipid metabolism, a majority of the studies related to TRF effects on lipids have focused only on individual tissues, and furthermore there is a lack of insight into potential underlying mechanisms. In this review, we summarize the current insights regarding TRF effects on lipid metabolism and the potential mechanisms in adipose tissue, liver, skeletal muscle, and heart, and conclude by outlining possible avenues for future exploration.
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Affiliation(s)
- Yiming Guo
- Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Christopher Livelo
- Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Girish Melkani
- Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Tao M, Liu J, Chen X, Wang Q, He M, Chen W, Wang C, Zhang L. Correlation between serum uric acid and body fat distribution in patients with MAFLD. BMC Endocr Disord 2023; 23:204. [PMID: 37749567 PMCID: PMC10518962 DOI: 10.1186/s12902-023-01447-7] [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: 03/22/2023] [Accepted: 08/31/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Metabolic dysfunction associated with fatty liver disease (MAFLD) is often correlated with obesity and hyperuricemia. The present study aimed to determine the association between serum uric acid (SUA) and central fat distribution in patients with MAFLD. METHODS A total of 485 patients were classified into the following groups: (1) controls without MAFLD and hyperuricemia (HUA), (2) MAFLD with normal SUA, and (3) MAFLD with HUA. DUALSCAN HDS-2000 was used to measure visceral fat (VAT) and subcutaneous fat (SAT). Dual-energy X-ray absorptiometry (DEXA) was used to measure body fat distribution. RESULTS MAFLD patients with HUA had remarkably higher BMI, fasting insulin, OGIRT AUC, ALT, AST, TG, VAT, SAT, Adipo-IR, trunk fat mass, android fat, and total body fat than MAFLD patients with normal SUA (all p < 0.05). The increase in VAT, SAT, CAP, Adipo-IR, upper limbs fat mass, trunk fat mass, and android fat, as well as the percentage of MAFLD, were significantly correlated with the increase in SUA. The percentage of MAFLD patients with HUA increased significantly with increasing VAT or SAT, as determined by the Cochran-Armitage trend test (all p < 0.05). Furthermore, VAT (OR = 1.01 CI: 1.00, 1.03; p < 0.05) and adipo-IR (OR = 1.09 CI: 1.00, 1.19; p < 0.05) were associated with circling SUA in MAFLD after adjusting for sex, age, TG, TC, HOMA-IR, and BMI. CONCLUSION Abdominal fat promotes the co-existence of HUA and MAFLD, while weight loss, especially, decreasing VAT, is of great importance to decrease SUA levels and manage MAFLD.
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Affiliation(s)
- Min Tao
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Jing Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Xingyu Chen
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Qing Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Miao He
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Wenwen Chen
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Cong Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
| | - Lili Zhang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
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Ge G, Ren J, Song G, Li Q, Cui Z. Transcriptome Analysis Reveals the Molecular Basis of Overfeeding-Induced Diabetes in Zebrafish. Int J Mol Sci 2023; 24:11994. [PMID: 37569372 PMCID: PMC10418320 DOI: 10.3390/ijms241511994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 08/13/2023] Open
Abstract
Diabetes has gradually become a serious disease that threatens human health. It can induce various complications, and the pathogenesis of diabetes is quite complex and not yet fully elucidated. The zebrafish has been widely acknowledged as a useful model for investigating the mechanisms underlying the pathogenesis and therapeutic interventions of diabetes. However, the molecular basis of zebrafish diabetes induced by overfeeding remains unknown. In this study, a zebrafish diabetes model was established by overfeeding, and the molecular basis of zebrafish diabetes induced by overfeeding was explored. Compared with the control group, the body length, body weight, and condition factor index of zebrafish increased significantly after four weeks of overfeeding. There was a significant elevation in the fasting blood glucose level, accompanied by a large number of lipid droplets accumulated within the liver. The levels of triglycerides and cholesterol in both the serum and liver exhibited a statistically significant increase. Transcriptome sequencing was employed to investigate changes in the livers of overfed zebrafish. The number of up-regulated and down-regulated differentially expressed genes (DEGs) was 1582 and 2404, respectively, in the livers of overfed zebrafish. The DEGs were subjected to KEGG and GO enrichment analyses, and the hub signaling pathways and hub DEGs were identified. The results demonstrate that sixteen genes within the signal pathway associated with fatty acid metabolism were found to be significantly up-regulated. Specifically, these genes were found to mainly participate in fatty acid transport, fatty acid oxidation, and ketogenesis. Furthermore, thirteen genes that play a crucial role in glucose metabolism, particularly in the pathways of glycolysis and glycogenesis, were significantly down-regulated in the livers of overfed zebrafish. These results indicate insulin resistance and inhibition of glucose entry into liver cells in the livers of overfed zebrafish. These findings elucidate the underlying molecular basis of zebrafish diabetes induced by overfeeding and provide a model for further investigation of the pathogenesis and therapeutics of diabetes.
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Affiliation(s)
- Guodong Ge
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Jing Ren
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Guili Song
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Qing Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Zongbin Cui
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
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Baldini F, Diab F, Serale N, Zeaiter L, Portincasa P, Diaspro A, Vergani L. Adipocyte-hepatocyte crosstalk in cellular models of obesity: Role of soluble factors. Life Sci 2023; 317:121464. [PMID: 36731646 DOI: 10.1016/j.lfs.2023.121464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Abstract
Hepatic steatosis is often a consequence of obesity. Adipose tissue is an important endocrine regulator of metabolic homeostasis in the body. In obesity, adipocytes become hypertrophic and develop an inflammatory phenotype, altering the panel of secreted adipokines. Moreover, excess fatty acids are, in part, released by adipocytes and delivered to the liver. These multiple pathways of adipose-liver crosstalk contribute to the development and progression of liver disease: TNFα induces hepatocyte dysfunction, excess of circulating fatty acids promotes hepatic steatosis and inflammation, whilst adipokines mediate and exacerbate liver injury. In this study, we investigated in vitro the effects and mechanisms of the crosstalk between adipocytes and hepatocytes, as a function of the different adipocyte status (mature vs hypertrophic) being mediated by soluble factors. We employed the conditioned medium method to test how mature and hypertrophic adipocytes distinctively affect the liver, leading to metabolic dysfunction. The media collected from adipocytes were characterized by high triglyceride content and led to lipid accumulation and fat-dependent dysfunction in hepatocytes. The present findings seem to suggest that, in addition to triglycerides, other soluble mediators, cytokines, are released by mature and hypertrophic adipocytes and influence the metabolic status of liver cells. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD in obesity will provide important insights into the mechanisms responsible for the metabolic complications of obesity, paving the way for new possible approaches.
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Affiliation(s)
- Francesca Baldini
- Nanoscopy, Istituto Italiano Tecnologia, Via Enrico Melen 83, 16152 Genova, Italy; Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy.
| | - Farah Diab
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy.
| | - Nadia Serale
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari, Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy.
| | - Lama Zeaiter
- Nanoscopy, Istituto Italiano Tecnologia, Via Enrico Melen 83, 16152 Genova, Italy; Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy.
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari, Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy.
| | - Alberto Diaspro
- Nanoscopy, Istituto Italiano Tecnologia, Via Enrico Melen 83, 16152 Genova, Italy; Department of Physics (DIFILAB), University of Genoa, Via Dodecaneso 33, 16146 Genoa, Italy; Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6 - Torre di Francia, 16149 Genova, Italy.
| | - Laura Vergani
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy.
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Chen R, Liao K, Liao H, Zhang L, Zhao H, Sun J. Screening and functional validation of lipid metabolism-related lncRNA-46546 based on the transcriptome analysis of early embryonic muscle tissue in chicken. Anim Biosci 2023; 36:175-190. [PMID: 35073667 PMCID: PMC9834732 DOI: 10.5713/ab.21.0440] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 01/07/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The study was conducted to screen differentially expressed long noncoding RNA (lncRNA) in chickens by high-throughput sequencing and explore its mechanism of action on intramuscular fat deposition. METHODS Herein, Rose crown and Cbb broiler chicken embryo breast and leg muscle lncRNA and mRNA expression profiles were constructed by RNA sequencing. A total of 96 and 42 differentially expressed lncRNAs were obtained in Rose crown vs Cobb broiler chicken breast and leg muscle, respectively. lncRNA-ENSGALT00000046546, with high interspecific variability and a potential regulatory role in lipid metabolism, and its predicted downstream target gene 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), were selected for further study on the preadipocytes. RESULTS lncRNA-46546 overexpression in chicken preadipocyte 2 cells significantly increased (p<0.01) the expression levels of AGPAT2 and its downstream genes diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 and those of the fat metabolism-related genes peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, fatty acid synthase, sterol regulatory element-binding transcription factor 1, and fatty acid binding protein 4. The lipid droplet concentration was higher in the overexpression group than in the control cells, and the triglyceride content in cells and medium was also significantly increased (p<0.01). CONCLUSION This study preliminarily concludes that lncRNA-46546 may promote intramuscular fat deposition in chickens, laying a foundation for the study of lncRNAs in chicken early embryonic development and fat deposition.
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Affiliation(s)
- Ruonan Chen
- College of Animal Science and Technology, Shihezi University, Shihezi, 832000,
China
| | - Kai Liao
- College of Pharmacy, Shihezi University, Shihezi, 832000,
China
| | - Herong Liao
- College of Animal Science and Technology, Shihezi University, Shihezi, 832000,
China
| | - Li Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi, 832000,
China
| | - Haixuan Zhao
- College of Medical, Shihezi University, Shihezi, 832000,
China
| | - Jie Sun
- College of Animal Science and Technology, Shihezi University, Shihezi, 832000,
China,Corresponding Author: Jie Sun, Tel: +86-135-7974-2370, E-mail:
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Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury-A Repeated Dose Study in Minipigs for 28 Days. Int J Mol Sci 2023; 24:ijms24021445. [PMID: 36674967 PMCID: PMC9863319 DOI: 10.3390/ijms24021445] [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: 11/22/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/14/2023] Open
Abstract
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ß-defensin. Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response.
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Sultana N, Islam R, Das RR, Haque Z, Rafiq K, Khan MAHNA. Steroid growth promoter modified glucose profile and liver morphology in broiler by altering the localization and expression pattern of hepatic glucocorticoid receptors. Res Vet Sci 2022; 152:277-288. [DOI: 10.1016/j.rvsc.2022.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 01/08/2023]
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21
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Arrighetti F, Landro SM, Lavarías SML. Sensitivity of histopathological and histochemical parameters in the digestive gland of the apple snail Pomacea canaliculata exposed to cypermethrin. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 252:106292. [PMID: 36137307 DOI: 10.1016/j.aquatox.2022.106292] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 08/23/2022] [Accepted: 09/08/2022] [Indexed: 06/16/2023]
Abstract
The aim of this study was to evaluate the toxic effects of the pesticide cypermethrin (CYP) in the digestive gland of the apple snail, Pomacea canaliculata, analysing histological and histochemical alterations. Adult snails were exposed to sublethal CYP concentrations (10, 25, and 100 µg/L) under acute (1 day) and sub-chronic (14 days) conditions. Histological analyses of the morphology of the digestive gland were performed and a histopathological condition index (HI) was calculated. Also, both intracellular accumulation of lipofuscins (LF) and neutral lipids (NL) were evaluated. CYP exposure induced tissue damage to this organ, such as disorganisation of the connective tissue, fibrosis, haemocytic infiltration, atrophy, and necrosis under acute and sub-chronic conditions. These alterations, integrated into a single HI value, revealed notable CYP effects during both acute and sub-chronic exposures. Cell type replacement, measured as VvBAS, was only observed in the sub-chronic treatment. Under acute conditions, the pyrethroid affected NL accumulation at the highest concentration, while in sub-chronic conditions NL accumulation was only observed at the lowest concentrations. P. canaliculata also showed a dose-dependent response of LF under acute CYP exposure conditions. However, under sub-chronic conditions, this parameter was not sensitive to pesticide exposure. All these relevant structural lesions may affect the normal function of the digestive gland, even though the species presented additional mechanisms, as infiltration of hemocyte and basophilic cell hyperplasia, that help it to tolerate the exposure to pollutants. This study showed that some histological and histochemical parameters are sensitive in P. canaliculata at CYP concentrations to which the snail could be exposed in the environments it inhabits.
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Affiliation(s)
- Florencia Arrighetti
- Museo Argentino de Ciencias Naturales "Bernardino Rivadavia" CONICET, CABA, Argentina.
| | - Sonia M Landro
- Museo Argentino de Ciencias Naturales "Bernardino Rivadavia" CONICET, CABA, Argentina
| | - Sabrina M L Lavarías
- Instituto de Limnología de La Plata"Dr. Raúl A. Ringuelet" (ILPLA) CCT CONICET La Plata-Universidad Nacional de La Plata (UNLP), La Plata, Argentina
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22
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Luo D, Yang L, Pang H, Zhao Y, Li K, Rong X, Guo J. Tianhuang formula reduces the oxidative stress response of NAFLD by regulating the gut microbiome in mice. Front Microbiol 2022; 13:984019. [PMID: 36212891 PMCID: PMC9533869 DOI: 10.3389/fmicb.2022.984019] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/08/2022] [Indexed: 12/11/2022] Open
Abstract
Background The gut microbiome affects the occurrence and development of NAFLD, but its mechanism has not yet been fully elucidated. Chinese medicine is a new treatment strategy to improve NAFLD by regulating the gut microbiome. Tianhuang formula (TH) has been proved to have a lipid-lowering effect in which constituents of ginsenoside Rb1, ginsenoside Rg1, ginsenoside Rb, ginsenoside Re, and ginsenoside R1 from Panax notoginseng and berberine, palmatine, and coptisine from Coptis chinensis have low drug permeability, which results in poor intestinal absorption into the human body, and are thus able to come into contact with the gut microflora for a longer time. Therefore, it might be able to influence the gut microbial ecosystem, but it still needs to be investigated. Method The characteristics of the gut microbiome were represented by 16S rRNA sequencing, and the metabolites in intestinal contents and liver were discovered by non-targeted metabolomics. Correlation analysis and fermentation experiments revealed the relationship between the gut microbiome and metabolites. Blood biochemical indicators, liver function indicators, and oxidation-related indicators were assayed. H&E staining and Oil Red O staining were used to analyze the characteristics of hepatic steatosis. RT-qPCR and western blotting were used to detect the expression of genes and proteins in liver tissues, and fecal microbial transplantation (FMT) was performed to verify the role of the gut microbiome. Results Gut microbiome especially Lactobacillus reduced, metabolites such as 5-Methoxyindoleacetate (5-MIAA) significantly reduced in the liver and intestinal contents, the level of hepatic GSH and SOD reduced, MDA increased, and the protein expression of Nrf2 also reduced in NAFLD mice induced by high-fat diet (HFD). The normal diet mice transplanted with NAFLD mice feces showed oxidative liver injury, indicating that the NAFLD was closely related to the gut microbiome. TH and TH-treated mice feces both can reshape the gut microbiome, increase the abundance of Lactobacillus and the content of 5-MIAA in intestinal contents and liver, and improve oxidative liver injury. This indicated that the effect of TH improving NAFLD was related to the gut microbiome, especially Lactobacillus. 5-MIAA, produced by Lactobacillus, was proved with fermentation experiments in vitro. Further experiments proved that 5-MIAA activated the Nrf2 pathway to improve oxidative stress in NAFLD mice induced by HFD. TH reshaped the gut microbiome, increased the abundance of Lactobacillus and its metabolite 5-MIAA to alleviate oxidative stress, and improved NAFLD. Conclusion The study has demonstrated a mechanism by which the gut microbiome modulated oxidative stress in NAFLD mice induced by HFD. The traditional Chinese medicine TH improved NAFLD by regulating the gut microbiome, and its mechanism was related to the “Lactobacillus-5-MIAA-Nrf2” pathway. It provided a promising way for the intervention of NAFLD.
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Gart E, van Duyvenvoorde W, Caspers MPM, van Trigt N, Snabel J, Menke A, Keijer J, Salic K, Morrison MC, Kleemann R. Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr-/-.Leiden mice with manifest obesity-associated NASH. FASEB J 2022; 36:e22435. [PMID: 35830259 DOI: 10.1096/fj.202200111r] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 11/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative-inflammatory stress. After a 26 weeks run-in on fast food diet (FFD), obese Ldlr-/-.Leiden mice were treated for another 12 weeks with either valine or isoleucine (3% of FFD) and then compared to FFD controls. Valine and isoleucine did not affect obesity, dyslipidemia, gut permeability, or fecal fatty acid excretion, but significantly reduced hyperinsulinemia. Valine and isoleucine reduced ALT, CK18-M30, and liver steatosis with a particularly pronounced suppression of the microvesicular component (-61% by valine and -71% by isoleucine). Both BCAAs decreased intrahepatic diacylglycerols and 4-hydroxynonenal immunoreactivity, a marker for oxidative stress-induced lipid peroxidation. Functional genomics analysis demonstrated that valine and isoleucine affected BCAA metabolism genes, deactivated master regulators of anabolic pathways related to steatosis (e.g., SREBPF1), and activated master regulators of mitochondrial biogenesis (e.g., PPARGC1A) and lipid catabolism (e.g., ACOX1, AMPK). This correction of critical metabolic pathways on gene expression level was accompanied by a significant decrease in histological liver inflammation, and suppression of FFD-stimulated cytokine and chemokine proteins KC/CXCL1, MCP-1/CCL2, and MIP-2/CXCL2 and their pathways. In conclusion, dietary intervention with either valine or isoleucine corrected liver diacylglycerols, gene expression of multiple metabolic processes, and reduced NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins.
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Affiliation(s)
- Eveline Gart
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Martien P M Caspers
- Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), Zeist, the Netherlands
| | - Nikki van Trigt
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Jessica Snabel
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Aswin Menke
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Kanita Salic
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Martine C Morrison
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands
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Shen Y, Sun Y, Wang X, Xiao Y, Ma L, Lyu W, Zheng Z, Wang W, Li J. Liver Transcriptome and Gut Microbiome Analysis Reveals the Effects of High Fructose Corn Syrup in Mice. Front Nutr 2022; 9:921758. [PMID: 35845805 PMCID: PMC9280673 DOI: 10.3389/fnut.2022.921758] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
High fructose corn syrup (HFCS) is a viscous mixture of glucose and fructose that is used primarily as a food additive. This article explored the effect of HFCS on lipid metabolism-expressed genes and the mouse gut microbiome. In total, ten 3-week-old male C57BL/6J mice were randomly divided into two groups, including the control group, given purified water (Group C) and 30% HFCS in water (Group H) for 16 weeks. Liver and colonic content were collected for transcriptome sequencing and 16S rRNA gene sequencing, respectively. HFCS significantly increased body weight, epididymal, perirenal fat weight in mice (p < 0.05), and the proportion of lipid droplets in liver tissue. The expression of the ELOVL fatty acid elongase 3 (Elovl3) gene was reduced, while Stearoyl-Coenzyme A desaturase 1 (Scd1), peroxisome proliferator activated receptor gamma (Pparg), fatty acid desaturase 2 (Fads2), acyl-CoA thioesterase 2 (Acot2), acyl-CoA thioesterase 2 (Acot3), acyl-CoA thioesterase 4 (Acot4), and fatty acid binding protein 2 (Fabp2) was increased in Group H. Compared with Group C, the abundance of Firmicutes was decreased in Group H, while the abundance of Bacteroidetes was increased, and the ratio of Firmicutes/Bacteroidetes was obviously decreased. At the genus level, the relative abundance of Bifidobacterium, Lactobacillus, Faecalibaculum, Erysipelatoclostridium, and Parasutterella was increased in Group H, whereas that of Staphylococcus, Peptococcus, Parabacteroides, Donghicola, and Turicibacter was reduced in Group H. Pparg, Acot2, Acot3, and Scd1 were positively correlated with Erysipelatoclostridium and negatively correlated with Parabacteroides, Staphylococcus, and Turicibacter. Bifidobacterium was negatively correlated with Elovl3. Overall, HFCS affects body lipid metabolism by affecting the expression of lipid metabolism genes in the liver through the gut microbiome.
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Affiliation(s)
- Yu Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Yangying Sun
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
| | - Xiaoli Wang
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Yingping Xiao
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Lingyan Ma
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Wentao Lyu
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Zibin Zheng
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Wen Wang
- Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Jinjun Li
- Institute of Food Sciences, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
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Baldini F, Khalil M, Bartolozzi A, Vassalli M, Di Ciaula A, Portincasa P, Vergani L. Relationship between Liver Stiffness and Steatosis in Obesity Conditions: In Vivo and In Vitro Studies. Biomolecules 2022; 12:733. [PMID: 35625660 PMCID: PMC9139073 DOI: 10.3390/biom12050733] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/11/2022] [Accepted: 05/20/2022] [Indexed: 02/08/2023] Open
Abstract
Obesity is a major risk factor for metabolic dysfunction such as non-alcoholic fatty liver disease (NAFLD). The NAFLD spectrum ranges from simple steatosis, to steatohepatitis, fibrosis, and cirrhosis. The aim of this study is to characterize the grade of steatosis being associated with overnutrition and obesity, both at the level of single hepatocyte and whole liver, and to correlate it with the hepatocyte/liver stiffness and dysfunction. For the in vivo study, 60 subjects were enrolled and grouped based on the stage of liver steatosis/fibrosis according to biochemical analyses, liver ultrasonography (USG) and acoustic radiation force impulse shear wave elastography (ARFI-SWE). For single hepatocyte analyses we employed in vitro models of moderate and severe steatosis on which to assess the single cell biomechanics by Single Cell Force Spectroscopy (SCFS) and Quantitative Phase Microscopy (QPM). Results show that in vivo liver stiffness depends mainly on the extent of fat accumulation and not on fibrosis. These results parallel the in vitro observations showing that hepatocyte stiffness and dysfunction increase with increasing fat accumulation and lipid droplet enlargement. Our findings indicate that the extent of steatosis markedly affects the biomechanical properties of both liver and single hepatocytes thus proving insights about the role of modulation of liver/hepatocyte elasticity as a physical mechanism transducing the obesity-dependent excess of plasmatic lipids towards liver steatosis and dysfunction.
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Affiliation(s)
- Francesca Baldini
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy;
- Nanoscopy, Istituto Italiano Tecnologia, Via Enrico Melen 83, 16152 Genova, Italy
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.K.); (A.D.C.); (P.P.)
| | - Alice Bartolozzi
- Dipartimento di Ingegneria dell’Informazione, Università degli Studi di Firenze, Via di S. Marta 3, 50139 Firenze, Italy;
| | - Massimo Vassalli
- James Watt School of Engineering, University of Glasgow, Glasgow G12 8LT, UK;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.K.); (A.D.C.); (P.P.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.K.); (A.D.C.); (P.P.)
| | - Laura Vergani
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy;
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Pressly JD, Gurumani MZ, Varona Santos JT, Fornoni A, Merscher S, Al-Ali H. Adaptive and maladaptive roles of lipid droplets in health and disease. Am J Physiol Cell Physiol 2022; 322:C468-C481. [PMID: 35108119 PMCID: PMC8917915 DOI: 10.1152/ajpcell.00239.2021] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Advances in the understanding of lipid droplet biology have revealed essential roles for these organelles in mediating proper cellular homeostasis and stress response. Lipid droplets were initially thought to play a passive role in energy storage. However, recent studies demonstrate that they have substantially broader functions, including protection from reactive oxygen species, endoplasmic reticulum stress, and lipotoxicity. Dysregulation of lipid droplet homeostasis is associated with various pathologies spanning neurological, metabolic, cardiovascular, oncological, and renal diseases. This review provides an overview of the current understanding of lipid droplet biology in both health and disease.
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Affiliation(s)
- Jeffrey D. Pressly
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Margaret Z. Gurumani
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Javier T. Varona Santos
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Alessia Fornoni
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Sandra Merscher
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Hassan Al-Ali
- 1Katz Division of Nephrology and Hypertension and Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida,2Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida,3Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, Florida,4The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida,5Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida
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Xu H, Wang L. The Role of Notch Signaling Pathway in Non-Alcoholic Fatty Liver Disease. Front Mol Biosci 2021; 8:792667. [PMID: 34901163 PMCID: PMC8652134 DOI: 10.3389/fmolb.2021.792667] [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: 10/11/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH), liver cirrhosis, or hepatocellular carcinoma (HCC). NAFLD is a kind of metabolic disordered disease, which is commonly associated with lipid metabolism, insulin resistance, oxidative stress, inflammation, and fibrogenesis, as well as autophagy. Growing studies have shown Notch signaling pathway plays a pivotal role in the regulation of NAFLD progression. Here, we review the profile of the Notch signaling pathway, new evidence of Notch signaling involvement in NAFLD, and describe the potential of Notch as a biomarker and therapeutic target for NAFLD treatment.
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Affiliation(s)
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
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Kotlyarov S, Bulgakov A. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease. Cells 2021; 10:2978. [PMID: 34831201 PMCID: PMC8616072 DOI: 10.3390/cells10112978] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia;
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Ilias N, Hamzah H, Ismail IS, Mohidin TBM, Idris MF, Ajat M. An insight on the future therapeutic application potential of Stevia rebaudiana Bertoni for atherosclerosis and cardiovascular diseases. Biomed Pharmacother 2021; 143:112207. [PMID: 34563950 DOI: 10.1016/j.biopha.2021.112207] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Stevia rebaudiana Bertoni is a native plant to Paraguay. The extracts have been used as a famous sweetening agent, and the bioactive components derived from stevia possess a broad spectrum of therapeutical potential for various illnesses. Among its medicinal benefits are anti-hypertensive, anti-tumorigenic, anti-diabetic, and anti-hyperlipidemia. Statins (3-hydro-3-methylglutaryl-coenzyme A reductase inhibitor) are a class of drugs used to treat atherosclerosis. Statins are explicitly targeting the HMG-CoA reductase, an enzyme in the rate-limiting step of cholesterol biosynthesis. Despite being widely used in regulating plasma cholesterol levels, the adverse effects of the drug are a significant concern among clinicians and patients. Hence, steviol glycosides derived from stevia have been proposed as an alternative in replacing statins. Diterpene glycosides from stevia, such as stevioside and rebaudioside A have been evaluated for their efficacy in alleviating cholesterol levels. These glycosides are a potential candidate in treating and preventing atherosclerosis provoked by circulating lipid retention in the sub-endothelial lining of the artery. The present review is an effort to integrate the pathogenesis of atherosclerosis, involvement of lipid droplets biogenesis and its associated proteins in atherogenesis, current approaches to treat atherosclerosis, and pharmacological potential of stevia in treating the disease.
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Affiliation(s)
- Nazhan Ilias
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Hazilawati Hamzah
- Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Intan Safinar Ismail
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Malaysia; Natural Medicines and Products Research Laboratory (NaturMeds), Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Taznim Begam Mohd Mohidin
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Mohd Faiz Idris
- Pusat Bahasa dan Pengajian Umum, Universiti Pendidikan Sultan Idris, 35900 Tanjong Malim, Malaysia
| | - Mokrish Ajat
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia; Natural Medicines and Products Research Laboratory (NaturMeds), Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Malaysia.
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Yang B, Sun J, Liang S, Wu P, Lv R, He Y, Li D, Sun W, Song X. Prediction of Srebp-1 as a Key Target of Qing Gan San Against MAFLD in Rats via RNA-Sequencing Profile Analysis. Front Pharmacol 2021; 12:680081. [PMID: 34290609 PMCID: PMC8289482 DOI: 10.3389/fphar.2021.680081] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/08/2021] [Indexed: 12/19/2022] Open
Abstract
Metabolism-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, and the use of traditional Chinese medicines (TCMs) to treat this disease has attracted increasing attention. The Qing Gan San (QGS) formula comprises Polygonatum sibiricum, the peel of Citrus reticulata Blanco, the leaves of Morus alba L, Cichorium intybus, Glycyrrhiza uralensis Fisch, and Cirsium setosum. The present study aimed to uncover the anti-hyperlipidaemic effects, hepatic fat accumulation-lowering effects and mechanisms of QGS in high-fat diet-induced MAFLD rats. QGS significantly reduced the levels of total cholesterol and triglycerides in both serum and liver tissue and partially protected hepatic function. Additionally, QGS significantly ameliorated hepatic lipid accumulation with histopathology observation, as demonstrated by H&E and oil red O staining. RNA sequencing was used to further investigate the key genes involved in the development and treatment of MAFLD. Hierarchical clustering analysis showed that the gene expression profiles in rats with MAFLD were reversed to normal after QGS treatment. QGS had 222 potential therapeutic targets associated with MAFLD. Enrichment analysis among these targets revealed that QGS affected biological functions/pathways such as the regulation of lipid metabolic processes (GO: 0019216) and the non-alcoholic fatty liver disease pathway (hsa04932), and identified Srebp-1 as a key regulator in the synthesis of cholesterol and triglycerides. Subsequently, both immunofluorescence and Western blot analyses demonstrated that QGS suppressed the transfer of Srebp-1 to the nucleus from the cytoplasm, suggesting that the activation of Srebp-1 was inhibited. Our study reveals the effects and mechanisms of QGS in the treatment of MAFLD and provides insights and prospects to further explore the pathogenesis of MAFLD and TCM therapies.
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Affiliation(s)
- Bendong Yang
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Jingyue Sun
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Shufei Liang
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Peixuan Wu
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Rui Lv
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Yanping He
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Deqi Li
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Wenlong Sun
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Xinhua Song
- School of Life Sciences, Shandong University of Technology, Zibo, China
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Lee S, Kim KW, Kim SY, Seo N, Song GW, Lee SG. Controlled attenuation parameter measured using transient elastography for the noninvasive assessment of macrovesicular steatosis in potential living liver donors. Ultrasonography 2021; 41:164-170. [PMID: 34399042 PMCID: PMC8696135 DOI: 10.14366/usg.21071] [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: 03/25/2021] [Accepted: 06/06/2021] [Indexed: 11/03/2022] Open
Abstract
PURPOSE This study aimed to determine the diagnostic performance of the controlled attenuation parameter (CAP) measured using transient elastography (TE) for assessing macrovesicular steatosis (MaS) in potential living liver donors using same-day biopsy as a reference standard. METHODS This retrospective study included 204 living liver donor candidates who underwent TE and liver biopsy on the same day between July 2013 and June 2014. The histologic degree of MaS was determined. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the performance of CAP for diagnosing MaS of >10%, and the optimal cutoff value was identified using the maximal Youden index. RESULTS Based on liver biopsy, 185 subjects had MaS of ≤10% and 19 had MaS of >10%. The CAP value was significantly correlated with the percentage of MaS on liver biopsy (r=0.635, P<0.001), and the median CAP value was significantly higher in subjects with MaS of >10% than in those with MaS of ≤10% (300 dB/m vs. 209 dB/m, P<0.001). The AUROC for diagnosing MaS of >10% by CAP was 0.938 (95% confidence interval, 0.896 to 0.967), and a CAP of >259 dB/m yielded a sensitivity of 84.2% and a specificity of 92.4%. CONCLUSION The CAP measured using TE was significantly correlated with MaS and accurately detected substantial MaS in potential living liver donors. The CAP is a promising tool for the noninvasive diagnosis of MaS and may be used to screen unsuitable living liver donor candidates.
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Affiliation(s)
- Sunyoung Lee
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyoung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Nieun Seo
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Mass Sanchez PB, Krizanac M, Weiskirchen R, Asimakopoulos A. Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights. Int J Mol Sci 2021; 22:5284. [PMID: 34067931 PMCID: PMC8156377 DOI: 10.3390/ijms22105284] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/07/2021] [Accepted: 05/16/2021] [Indexed: 12/24/2022] Open
Abstract
Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.
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Affiliation(s)
| | | | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany; (P.B.M.S.); (M.K.)
| | - Anastasia Asimakopoulos
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany; (P.B.M.S.); (M.K.)
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Gong L, Wang Z, Wang Z, Zhang Z. Sestrin2 as a Potential Target for Regulating Metabolic-Related Diseases. Front Endocrinol (Lausanne) 2021; 12:751020. [PMID: 34803916 PMCID: PMC8595836 DOI: 10.3389/fendo.2021.751020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Sestrin2 is a highly conserved protein that can be induced under a variety of stress conditions, including DNA damage, oxidative stress, endoplasmic reticulum (ER) stress, and metabolic stress. Numerous studies have shown that the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway has a crucial role in the regulation of metabolism. Sestrin2 regulates metabolism via a number of pathways, including activation of AMPK, inhibition of the mTOR complex 1 (mTORC1), activation of mTOR complex 2 (mTORC2), inhibition of ER stress, and promotion of autophagy. Therefore, modulation of Sestrin2 activity may provide a potential therapeutic target for the prevention of metabolic diseases such as insulin resistance, diabetes, obesity, non-alcoholic fatty liver disease, and myocardial ischemia/reperfusion injury. In this review, we examined the regulatory relationship between Sestrin2 and the AMPK/mTOR signaling pathway and the effects of Sestrin2 on energy metabolism.
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Xie W, Chen S. A nomogram for estimating the probability of nonalcoholic fatty liver disease in a Chinese population: A retrospective cohort study. Medicine (Baltimore) 2020; 99:e23049. [PMID: 33235066 PMCID: PMC7710235 DOI: 10.1097/md.0000000000023049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/06/2020] [Accepted: 10/08/2020] [Indexed: 12/19/2022] Open
Abstract
Studies have showed that dyslipidemia is closely related to nonalcoholic fatty liver disease (NAFLD). However, less attention has been paid to the relationship between early dyslipidemia and long-term risk of NAFLD. Therefore, we aimed to develop a simple-to-use nomogram to predict early dyslipidemia and long-term risk of NAFLD onset.A retrospective cohort study including 3621 employees (including retirees) from 7 companies was conducted between 2012 and 2019. Anthropometric, potential laboratory parameters and abdominal ultrasound were performed at baseline and after a 5-year follow-up. Cox proportional hazards model was used to determine predictors for NAFLD onset. The effects of lipids, age, body mass index (BMI), and serum uric acid (UA) on NAFLD were evaluated with the use of Kaplan-Meier curves (log-rank test). A nomogram was developed based on the Cox proportional hazard model and a 2-piecewise linear regression model. The accuracy of model was evaluated according to the area under the receiver operating characteristic curves.A total of 1545 subjects were included in the final analysis. The mean follow-up time was 52 ± 6.6 months. Of the total subjects, 77.61% were male and 22.39% were female. The mean age at the time of initial visit was 45.21 ± 11.20 years. Five hundred fifty-five subjects (35.92% of all subjects) were finally diagnosed with NAFLD. Variables in the nomogram included age, BMI, triglycerides, high-density lipoprotein, low-density lipoprotein, and UA. The accuracy of the nomogram for predicting 5-year cumulative occurrence of NAFLD was 0.8135 (95% confidence interval: 0.7921-0.8349), and the sensitivity and specificity were 0.8108 and 0.6960, respectively.The combination of age, BMI, triglycerides, high-density lipoprotein, low-density lipoprotein, and UA translated into a nomogram can reliably estimate the incidence of NAFLD within 5 years. It may serve as a decision support tool to determine whether to intervene at an early stage.
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He Y, Yang W, Gan L, Liu S, Ni Q, Bi Y, Han T, Liu Q, Chen H, Hu Y, Long Y, Yang L. Silencing HIF-1α aggravates non-alcoholic fatty liver disease in vitro through inhibiting PPAR-α/ANGPTL4 singling pathway. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 44:355-365. [PMID: 33272734 DOI: 10.1016/j.gastrohep.2020.09.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/02/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is an aberrant lipid metabolism disease. Hypoxia inducible factor-1 (HIF-1α) is a transcription factor which plays an important part in adapting lower oxygen condition. Here, we aimed to clarify the relationship between HIF-1α and NAFLD. METHODS HepG2 cells was stimulated by oleic acid (OA) and palmitic acid (PA) to establish in vitro model of NAFLD. The expression of lipid metabolism-related genes, the binding of PPARα to HIF-1α promoter, the lipid deposition, and oxidative stress were detected by qRT-PCR, western blot, Chip assay, Oil Red O staining and ELISA assays, respectively. RESULTS HIF-1α silence promoted lipid accumulation in NAFLD cells, accompanying by the significantly increased contents of TG (triglyceride) and ApoB (apolipoprotein B). In HepG2 cells treated with OA/PA, the expression of lipid metabolism-related genes and proteins, including APOE, A2m, TNFRSF11B, LDLr, and SREBP2, and the intracellular lipid deposition were up-regulated and further aggravated after silencing HIF-1α. In addition, the loss of HIF-1α could remarkably elevate MDA contents while inhibit the activities of beneficial antioxidant enzymes SOD and GSH-Px to activate oxidative stress, and promote the secretion of pro-inflammatory IL-6 and TNF-α to aggravate inflammation in NDFLD cells. PPARα positively bound to HIF-1α promoter. The silence of PPARα aggravated lipid deposition under normal or hypoxic environment in NAFLD cells. In addition, PPAR-α silence could decrease the expression of HIF-1α and ANGPTL4 in NAFLD cell model; moreover, the expression of APOE, A2m and TNFRSF11B and the production of TG and MDA were increased by PPAR-α suppression. CONCLUSION HIF-1α plays a crucial role in the regulation of lipid metabolism through activating PPAR-α/ANGPTL4 signaling pathway in NAFLD.
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Affiliation(s)
- Yan He
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Wenhui Yang
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Lulu Gan
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Shijie Liu
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Qing Ni
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Yunxia Bi
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Tun Han
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Qian Liu
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Hongyan Chen
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Yang Hu
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Yun Long
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China
| | - Li Yang
- Yan'an Hospital Affiliated to Kunming Medical University, Yunnan Cardiovascular Hospital, Key Laboratory of Cardiovascular Disease of Yunnan Province, Heart Disease Clinical Medical Center of Yunnan Province, Elderly Cardiovascular Disease Technology Innovation Team of Kunming, Key Laboratory of Cancer immunodeficiency of Yunnan Province, Kunming, Yunnan, PR. China.
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Tête A, Gallais I, Imran M, Legoff L, Martin-Chouly C, Sparfel L, Bescher M, Sergent O, Podechard N, Lagadic-Gossmann D. MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement. Food Chem Toxicol 2020; 146:111798. [PMID: 33022287 DOI: 10.1016/j.fct.2020.111798] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/17/2020] [Accepted: 09/29/2020] [Indexed: 02/06/2023]
Abstract
Liver steatosis has been associated with various etiological factors (obesity, alcohol, environmental contaminants). How those factors work together to induce steatosis progression is still scarcely evaluated. Here, we tested whether phthalates could potentiate death of steatotic hepatocytes when combined with ethanol. Pre-steatotic WIF-B9 hepatocytes were co-exposed to mono (2-ethylhexyl) (MEHP, 500 nM; main metabolite of di (2-ethylhexyl) phthalate or DEHP) and ethanol (5 mM) for 5 days. An increased apoptotic death was detected, involving a DNA damage response. Using 4-Methypyrazole to inhibit ethanol metabolism, and CH-223191 to antagonize the AhR receptor, we found that an AhR-dependent increase in alcohol dehydrogenase (ADH) activity was essential for cell death upon MEHP/ethanol co-exposure. Toxicity was also prevented by HET0016 to inhibit the cytochrome P450 4A (CYP4A). Using the antioxidant thiourea, a role for oxidative stress was uncovered, notably triggering DNA damage. Finally, co-exposing the in vivo steatosis model of high fat diet (HFD)-zebrafish larvae to DEHP (2.56 nM)/ethanol (43 mM), induced the pathological progression of liver steatosis alongside an increased Cyp4t8 (human CYP4A homolog) mRNA expression. Altogether, these results further emphasized the deleterious impact of co-exposures to ethanol/environmental pollutant towards steatosis pathological progression, and unraveled a key role for ADH and CYP4A in such effects.
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Affiliation(s)
- Arnaud Tête
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Isabelle Gallais
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Muhammad Imran
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Louis Legoff
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Corinne Martin-Chouly
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Lydie Sparfel
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Maëlle Bescher
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Odile Sergent
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Normand Podechard
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France
| | - Dominique Lagadic-Gossmann
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
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Vergani L, Baldini F, Khalil M, Voci A, Putignano P, Miraglia N. New Perspectives of S-Adenosylmethionine (SAMe) Applications to Attenuate Fatty Acid-Induced Steatosis and Oxidative Stress in Hepatic and Endothelial Cells. Molecules 2020; 25:molecules25184237. [PMID: 32942773 PMCID: PMC7570632 DOI: 10.3390/molecules25184237] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 12/26/2022] Open
Abstract
S-adenosylmethionine (SAMe) is an endogenous methyl donor derived from ATP and methionine that has pleiotropic functions. Most SAMe is synthetized and consumed in the liver, where it acts as the main methylating agent and in protection against the free radical toxicity. Previous studies have shown that the administration of SAMe as a supernutrient exerted many beneficial effects in various tissues, mainly in the liver. In the present study, we aimed to clarify the direct effects of SAMe on fatty acid-induced steatosis and oxidative stress in hepatic and endothelial cells. Hepatoma FaO cells and endothelial HECV cells exposed to a mixture of oleate/palmitate are reliable models for hepatic steatosis and endothelium dysfunction, respectively. Our findings indicate that SAMe was able to significantly ameliorate lipid accumulation and oxidative stress in hepatic cells, mainly through promoting mitochondrial fatty acid entry for β-oxidation and external triglyceride release. SAMe also reverted both lipid accumulation and oxidant production (i.e., ROS and NO) in endothelial cells. In conclusion, these outcomes suggest promising beneficial applications of SAMe as a nutraceutical for metabolic disorders occurring in fatty liver and endothelium dysfunction.
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Affiliation(s)
- Laura Vergani
- Department of Earth, Environment and Life Science, University of Genoa, 16132 Genova, Italy;
- Correspondence: ; Tel.: +39-0103538403; Fax: +39-0103538267
| | - Francesca Baldini
- Department of Experimemtal Medicine, University of Genoa, 16132 Genova, Italy;
| | - Mohamad Khalil
- School of Pharmacy, University of Camerino, 62032 Camerino, Italy;
| | - Adriana Voci
- Department of Earth, Environment and Life Science, University of Genoa, 16132 Genova, Italy;
| | | | - Niccolò Miraglia
- Clinical & Pre-clinical Development, Gnosis by Lesaffre S.p.A, 20832 Desio, Italy;
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The Interplay between Oxidative Stress and miRNAs in Obesity-Associated Hepatic and Vascular Complications. Antioxidants (Basel) 2020; 9:antiox9070607. [PMID: 32664383 PMCID: PMC7402144 DOI: 10.3390/antiox9070607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Nowadays, the obesity pandemic is one of the most relevant health issues worldwide. This condition is tightly related to comorbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), namely atherosclerosis. Dysregulated lipid metabolism and inflammation link these three diseases, leading to a subsequent increase of oxidative stress (OS) causing severe cellular damage. On the other hand, microRNAs (miRNAs) are short, single-stranded, non-coding RNAs that act as post-transcriptional negative regulators of gene expression, thus being involved in the molecular mechanisms that promote the development of many pathologies including obesity and its comorbidities. The involvement of miRNAs in promoting or opposing OS in disease progression is becoming more evident. Some miRNAs, such as miR-200a and miR.421, seem to play important roles in OS control in NAFLD. On the other hand, miR-92a and miR-133, among others, are important in the development of atherosclerosis. Moreover, since both diseases are linked to obesity, they share common altered miRNAs, being miR-34a and miR-21 related to OS. This review summarizes the latest advances in the knowledge about the mechanisms of oxidative stress (OS) generation in obesity-associated NAFLD and atherosclerosis, as well as the role played by miRNAs in the regulation of such mechanisms.
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Arumugam MK, Talawar S, Listenberger L, Donohue TM, Osna NA, Kharbanda KK. Role of Elevated Intracellular S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver Disease. Cells 2020; 9:1526. [PMID: 32585865 PMCID: PMC7349643 DOI: 10.3390/cells9061526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The earliest manifestation of alcohol-related liver disease (ALD) is steatosis, characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Findings from our laboratory have indicated that many pathological changes, including steatosis, correlate with the alcohol-induced hepatocellular increases in S-adenosylhomocysteine (SAH). Based on these considerations, we hypothesized that an experimental increase in intracellular SAH alone will result in similar steatotic changes to those seen after alcohol exposure. METHODS Freshly isolated rat hepatocytes grown on collagen-coated plates were exposed to serum-free medium containing 50 µmol/L oleic acid and varying concentrations of 3-deazaadenosine (DZA) to experimentally elevate intracellular SAH levels. RESULTS Overnight exposure to DZA treatment dose-dependently increased hepatocellular triglyceride accumulation, which was also evident by morphological visualization of larger-sized LDs. The rise in triglycerides and LDs accompanied increases in mRNA and protein levels of several LD-associated proteins known to regulate LD number and size. Furthermore, DZA treatment caused a decline in the levels of lipases that prevent fat accumulation as well as increased the expression of factors involved in lipogenesis and fatty acid mobilization. Collectively, our results indicate that the elevation of intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which is similar to that seen after alcohol exposure.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sharanappa Talawar
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Laura Listenberger
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA;
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Luo X, Liu Z, Ge X, Huang S, Zhou Y, Li D, Li L, Chen X, Huang L, Hou Q, Cheng H, Xiao L, Liu C, Zou Y, Yang X. High manganese exposure decreased the risk of high triglycerides in workers: a cross-sectional study. BMC Public Health 2020; 20:874. [PMID: 32503499 PMCID: PMC7275562 DOI: 10.1186/s12889-020-09011-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 05/29/2020] [Indexed: 01/04/2023] Open
Abstract
Background Manganese (Mn) participates in lipid metabolism. However, the associations between Mn exposure and dyslipidaemia is unclear. Methods This was a cross-sectional study. Data were collected from the 2017 the Mn-exposed workers healthy cohort (MEWHC). Finally, 803 occupationally Mn-exposed workers included in the study. The workers were divided into two groups. The grouping of this study was based on Mn-Time Weighted Averages (Mn-TWA). The high-exposure group included participants with Mn-TWA greater than 0.15 mg/m3. The low-exposure group included participants with Mn-TWA less than or equal to 0.15 mg/m3. Mn-TWA levels and dyslipidaemia were assessed. Results After adjustment for seniority, sex, cigarette consumption, alcohol consumption, high-fat diet frequency, medicine intake in the past two weeks, egg intake frequency, drinking tea, WHR, and hypertension, Mn-TWA levels was negatively correlated with high triglycerides (TG) risk in workers overall (OR = 0.51; 95% CI: 0.36, 0.73; p < 0.01). The results of males and females were consistent (OR = 0.53; 95% CI: 0.34, 0.81; p < 0.01) and (OR = 0.47; 95% CI: 0.24, 0.94; p < 0.01), respectively. By performing interactions analyses of workers overall, we observed no significant interactions among confounders. Mn-TWA levels and pack-years on high TG risk (relative excess risk for the interactions (RERI = 2.29, 95% CI: − 2.07, 6.66), (RERI) = 2.98, 95% CI: − 2.30, 8.26). Similarly, smoking status, drinking status, high-fat diet frequency, and Waist-to-Hip Ratio (WHR) showed non-significant interactions with Mn-TWA levels on high TG risk. Conclusions This research indicates that high Mn exposure was negatively related to high TG risk in workers.
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Affiliation(s)
- Xiaoyu Luo
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Zhenfang Liu
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaoting Ge
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Sifang Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Yanting Zhou
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Defu Li
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Longman Li
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiang Chen
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Lulu Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Qingzhi Hou
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Hong Cheng
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Lili Xiao
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Chaoqun Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Yunfeng Zou
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaobo Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China. .,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China. .,Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China.
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Neuman MG, Seitz HK, French SW, Malnick S, Tsukamoto H, Cohen LB, Hoffman P, Tabakoff B, Fasullo M, Nagy LE, Tuma PL, Schnabl B, Mueller S, Groebner JL, Barbara FA, Yue J, Nikko A, Alejandro M, Brittany T, Edward V, Harrall K, Saba L, Mihai O. Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research. Biomedicines 2020; 8:63. [PMID: 32197424 PMCID: PMC7148515 DOI: 10.3390/biomedicines8030063] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 02/07/2023] Open
Abstract
The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.
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Affiliation(s)
- Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, ON M5G 1L5, Canada;
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L5, Canada
| | - Helmut Karl Seitz
- Department of Medicine, Centre of Alcohol Research, University of Heidelberg, Salem Medical Centre, 337374 Heidelberg, Germany; (H.K.S.); (S.M.)
| | - Samuel W. French
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Stephen Malnick
- Department Internal Medicine C, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot 76100, Israel;
| | - Heidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-5311, USA;
- Department of Veterans; Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Lawrence B. Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON M4N 3M5, Canada;
| | - Paula Hoffman
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Boris Tabakoff
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Michael Fasullo
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12205, USA;
| | - Laura E. Nagy
- Departments of Pathobiology and Gastroenterology, Center for Liver Disease Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Pamela L. Tuma
- Department of Biology, The Catholic University of America, Washington, DC 20064, USA; (P.L.T.); (J.L.G.)
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA;
| | - Sebastian Mueller
- Department of Medicine, Centre of Alcohol Research, University of Heidelberg, Salem Medical Centre, 337374 Heidelberg, Germany; (H.K.S.); (S.M.)
| | - Jennifer L. Groebner
- Department of Biology, The Catholic University of America, Washington, DC 20064, USA; (P.L.T.); (J.L.G.)
| | - French A. Barbara
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Jia Yue
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Afifiyan Nikko
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Mendoza Alejandro
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Tillman Brittany
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Vitocruz Edward
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Kylie Harrall
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Laura Saba
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Opris Mihai
- In Vitro Drug Safety and Biotechnology, Toronto, ON M5G 1L5, Canada;
- Department Family Medicine Clinic CAR, 010164 Bucharest, Romania
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He M, Wang C, Long XH, Peng JJ, Liu DF, Yang GY, Jensen MD, Zhang LL. Mesencephalic astrocyte-derived neurotrophic factor ameliorates steatosis in HepG2 cells by regulating hepatic lipid metabolism. World J Gastroenterol 2020; 26:1029-1041. [PMID: 32205994 PMCID: PMC7081003 DOI: 10.3748/wjg.v26.i10.1029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/15/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a global metabolism-associated liver disease. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered secreted protein that is involved in metabolic homeostasis. However, much remains to be discovered about its function in hepatic lipid metabolism; thus, we assessed whether MANF could regulate hepatic metabolism. AIM To establish in vivo and in vitro NAFLD models to explore the role of MANF in hepatic lipid metabolism. METHODS HepG2 cells treated with free fatty acids (FFAs) and ob/ob mice were used as NAFLD models. Liver tissues collected from wild type and ob/ob mice were used to detect MANF expression. Cells were treated with FFAs for different durations. Moreover, we used lentiviral constructs to establish overexpression and knockdown cell models in order to interfere with MANF expression levels and observe whether MANF influences hepatic steatosis. Western blot analysis and quantitative real-time PCR were used to detect protein and gene expression, and oil red O staining was used to visualize intracellular lipid droplets. RESULTS Hepatic MANF protein and mRNA expression in wild type mice were 10-fold and 2-fold higher, respectively, than those in ob/ob mice. The MANF protein was temporarily increased by 1.3-fold after stimulation with FFAs for 24 h and gradually decreased to 0.66-fold that of the control at the 72 h time point in HepG2 cells. MANF deficiency upregulated the expression of genes involved in fatty acid synthesis, cholesterol synthesis, and fatty acid uptake and aggravated HepG2 cell steatosis, while MANF overexpression inhibited fatty acid synthesis and uptake and cholesterol synthesis, and rescued HepG2 cells from FFAs-induced steatosis. Furthermore, a significant decrease in triglyceride levels was observed in the MANF overexpression group compared with the control group (0.4288 ± 0.0081 mmol/g vs 0.3746 ± 0.0121 mmol/g, P < 0.05) upon FFAs treatment. There was also a 17% decrease in intracellular total cholesterol levels between the MANF overexpression group and the control group (0.1301 ± 0.0059 mmol/g vs 0.1088 ± 0.0009 mmol/g, P < 0.05) upon FFAs treatment. Moreover, MANF suppressed lipid deposition in HepG2 cells. CONCLUSION Our findings indicate that MANF improves the phenotype of liver cell steatosis and may be a potential therapeutic target in hepatic steatosis processes.
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Affiliation(s)
- Miao He
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Cong Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Xiao-Hong Long
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Jia-Jia Peng
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Dong-Fang Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Gang-Yi Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Michael D Jensen
- Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, United States
| | - Li-Li Zhang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
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Olsvik P, Hammer S, Sanden M, Søfteland L. Chlorpyrifos-induced dysfunction of lipid metabolism is not restored by supplementation of polyunsaturated fatty acids EPA and ARA in Atlantic salmon liver cells. Toxicol In Vitro 2019; 61:104655. [DOI: 10.1016/j.tiv.2019.104655] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/06/2019] [Accepted: 09/15/2019] [Indexed: 12/22/2022]
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Fromenty B. Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.06.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol 2019; 15:689-700. [PMID: 31554932 DOI: 10.1038/s41574-019-0256-9] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasing global public health burden. NAFLD is strongly associated with type 2 diabetes mellitus, obesity and cardiovascular disease and begins with intrahepatic triacylglycerol accumulation. Under healthy conditions, the liver regulates lipid metabolism to meet systemic energy needs in the fed and fasted states. The processes of fatty acid uptake, fatty acid synthesis and the intracellular partitioning of fatty acids into storage, oxidation and secretion pathways are tightly regulated. When one or more of these processes becomes dysregulated, excess lipid accumulation can occur. Although genetic and environmental factors have been implicated in the development of NAFLD, it remains unclear why an imbalance in these pathways begins. The regulation of fatty acid partitioning occurs at several points, including during triacylglycerol synthesis, lipid droplet formation and lipolysis. These processes are influenced by enzyme function, intake of dietary fats and sugars and whole-body metabolism, and are further affected by the presence of obesity or insulin resistance. Insight into how the liver controls fatty acid metabolism in health and how these processes might be affected in disease would offer the potential for new therapeutic treatments for NAFLD to be developed.
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Affiliation(s)
- Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, UK.
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
| | - Pippa J Gunn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK
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Baldini F, Bartolozzi A, Ardito M, Voci A, Portincasa P, Vassalli M, Vergani L. Biomechanics of cultured hepatic cells during different steatogenic hits. J Mech Behav Biomed Mater 2019; 97:296-305. [PMID: 31151002 DOI: 10.1016/j.jmbbm.2019.05.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/16/2019] [Accepted: 05/21/2019] [Indexed: 12/20/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease often associated with overnutrition. Number and morphometry of lipid droplets (LDs) define micro vs macrovesicular steatosis, influence the morphology and function of hepatocytes and possibly their stiffness. The link between grade and features of steatosis and biomechanical properties of single hepatocytes requires deeper investigations. In vitro NAFLD models with distinct steatosis conditions were set by exposing FaO hepatoma cells to single or combined fructose (Fru), fatty acids (FA), and tumor necrosis factor (TNF)α. Single Cell Force Spectroscopy and Quantitative Phase Microscopy quantified the single cell stiffness and a series of morphometric parameters; the mRNA expression of genes involved in lipid metabolism was quantified by real-time PCR. In our models, LD size and number increased with Fru and FA as single agents, and more with combined Fru/FA (macrovesicular steatosis), while FA/TNFα combination increased LD number with a reduction in their size (microvesicular steatosis). We found that the changes in LD size and number influenced cell stiffness and morphometry as follows: (i) single cell elasticity increased in macrovesicular steatosis (maximally with combined Fru/FA); (ii) FA-induced steatosis resulted in cells thinner and larger, whereas combined FA/TNFα shrunk the hepatocytes. Taken together the data on hepatocyte biomechanics show that, in addition to extent of lipid accumulation, cell stiffness is mainly influenced by LD size, while cell morphometry directly relates to LD number. Our findings suggest that a novel mechanobiology perspective might provide future contributions in NAFLD research.
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Affiliation(s)
- Francesca Baldini
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy
| | - Alice Bartolozzi
- Institute of Biophysics (IBF), National Research Council, Via De Marini 6, 16149, Genova, Italy
| | - Martina Ardito
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy
| | - Adriana Voci
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Massimo Vassalli
- Institute of Biophysics (IBF), National Research Council, Via De Marini 6, 16149, Genova, Italy
| | - Laura Vergani
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy.
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Lee DH, Jung YY, Park MH, Jo MR, Han SB, Yoon DY, Roh YS, Hong JT. Peroxiredoxin 6 Confers Protection Against Nonalcoholic Fatty Liver Disease Through Maintaining Mitochondrial Function. Antioxid Redox Signal 2019; 31:387-402. [PMID: 31007045 DOI: 10.1089/ars.2018.7544] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aims: Nonalcoholic fatty liver disease (NAFLD) is accompanied by excessive reactive oxygen species (ROS) production, which has been suggested in several studies to link with mitochondrial function. However, the mechanistic role of ROS-mediated regulation of mitochondrial function in NAFLD has not been elucidated. Since peroxiredoxin 6 (PRDX6) is the only member of the antioxidant PRDX family that translocates to damaged mitochondria, we investigated the PRDX6-mediated antisteatotic mechanism using genetically modified mice and cells. Results: PRDX6 mice were more protective to lipid accumulation, liver injury, and insulin resistance after a high-fat diet. Mechanistically, PRDX6 is required for induction of mitochondrial antioxidant action and beta-oxidation through maintaining mitochondrial integrity and subsequently prevents ROS-induced lipogenesis. Interestingly, oxidative stress-induced Notch signaling was suppressed in PRDX6 mice compared with wild-type mice, and genetic and pharmacological inhibition of Notch signaling improved lipid accumulation. Finally, PRDX knockdown or Notch inhibition reduced induction of mitophagy. PRDX6 antagonizes positive feedback loop between lipid accumulation and ROS production through regulation of mitochondrial function. Innovation: For the first time, we demonstrate that PRDX6 maintains mitochondria integrity under oxidative stress and protects against NAFLD progression by inhibition of Notch signaling. Conclusion: This study describes a novel molecular mechanism underlying the antisteatotic activity of PRDX6, which may be a new therapeutic strategy for the treatment of NAFLD.
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Affiliation(s)
- Dong Hun Lee
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
| | - Yu Yeon Jung
- 2 Department of Dental Hygiene, Gwangyang Health Sciences University, Gwangyang, South Korea
| | - Mi Hee Park
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
| | - Mi Ran Jo
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
| | - Sang Bae Han
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
| | - Do Young Yoon
- 3 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, South Korea
| | - Yoon Seok Roh
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
| | - Jin Tae Hong
- 1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea
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Ozturk K, Soylu E, Yazici Z, Ozkaya G, Savci G. Differentiation of hepatocellular carcinoma from non-hepatocellular malignant tumours of liver by chemical-shift MRI at 3 T. Clin Radiol 2019; 74:797-804. [PMID: 31300210 DOI: 10.1016/j.crad.2019.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/12/2019] [Indexed: 12/18/2022]
Abstract
AIM To evaluate the diagnostic performance of chemical shift magnetic resonance imaging (MRI) in distinguishing hepatocellular carcinomas (HCCs) from non-hepatocellular malignant tumours (non-HCCs) of the liver. MATERIALS AND METHODS Patients with a diagnosis of malignant liver tumours examined at 3 T MRI were included in this retrospective study. Forty-seven HCCs and 75 non-HCCs that were studied with chemical-shift MRI between January 2012 and October 2016 were retrieved from the radiology database. Two blinded observers measured the signal intensities of the tumours, adjacent normal-looking liver parenchyma, and spleen on chemical-shift MRI. The fat quantification for HCCs, non-HCCs, and adjacent normal-looking liver parenchyma were calculated by using the spleen as a reference standard. The subtraction scores were calculated by subtracting fat percentages in liver parenchyma from those in tumours. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the fat percentage subtraction scores in distinguishing HCCs from non-HCCs were calculated. RESULTS According to the optimal cut-off value acquired from both readers, a subtraction score >-0.26 was considered to be a HCC. Fat signal percentage subtraction scores were ≥-0.26 in 45 of 47 HCCs and were <-0.26 in 69 of 75 non-HCCs. The sensitivity, specificity, PPV, and NPV of fat signal percentage subtraction score to differentiate HCCs from non-HCCs were found to be 95.7%, 89.3%, 84.9%, and 97.1%, respectively. CONCLUSION Intracytoplasmic lipid in HCCs demonstrated by quantitative chemical-shift MRI may be a potentially powerful imaging biomarker to distinguish HCCs from the other malignant liver tumours.
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Affiliation(s)
- K Ozturk
- Department of Radiology, Uludag University Faculty of Medicine, Gorukle Street, Bursa, Turkey.
| | - E Soylu
- Department of Radiology, Uludag University Faculty of Medicine, Gorukle Street, Bursa, Turkey
| | - Z Yazici
- Department of Radiology, Uludag University Faculty of Medicine, Gorukle Street, Bursa, Turkey
| | - G Ozkaya
- Department of Biostatistics, Uludag University Faculty of Medicine, Gorukle Street, Bursa, Turkey
| | - G Savci
- Department of Radiology, Uludag University Faculty of Medicine, Gorukle Street, Bursa, Turkey
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Haemmerle G, Lass A. Genetically modified mouse models to study hepatic neutral lipid mobilization. Biochim Biophys Acta Mol Basis Dis 2019; 1865:879-894. [PMID: 29883718 PMCID: PMC6887554 DOI: 10.1016/j.bbadis.2018.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/25/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
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Affiliation(s)
- Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria.
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria; BioTechMed-Graz, Austria.
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Yang SS, Yu CB, Luo Z, Luo WL, Zhang J, Xu JX, Xu WN. Berberine attenuates sodium palmitate-induced lipid accumulation, oxidative stress and apoptosis in grass carp(Ctenopharyngodon idella)hepatocyte in vitro. FISH & SHELLFISH IMMUNOLOGY 2019; 88:518-527. [PMID: 30880233 DOI: 10.1016/j.fsi.2019.02.055] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 06/09/2023]
Abstract
The objective of this work was to investigate the effect of berberine (BBR) on the Cell viability, lipid accumulation, apoptosis, cytochrome c, caspase-9 and caspase-3 in lipid accumulation-hepatocytes induced by sodium palmitate in vitro. The lipid accumulation-hepatocytes (induced by 0.5 mM sodium palmitate for 24 h) were treated with 5 μM berberine for 12 h. Then, the Cell viability, intracellular triglyceride (TG) content, lipid peroxide (LPO), malonaldehyde (MDA) content, cytochrome c, caspase-9, caspase-3 and apoptosis were detected. Sodium palmitate decreased Cell viability and increased intracellular TG content, lipid droplet accumulation, LPO and MDA concentrations, caused caspase-3 and caspase-9 activation, then led to apoptosis accompanied by cytochrome c release from mitochondria into the cytoplasm. Beberine could improve intracellular lipid droplet accumulation and oxidative stress, while reduce apoptosis induced by sodium palmitate.
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Affiliation(s)
- Shuo-Shuo Yang
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Cheng-Bing Yu
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Zhen Luo
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Wen-Li Luo
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Jing Zhang
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Jian-Xiong Xu
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Wei-Na Xu
- Shanghai Key Laboratory for Veterinary and Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai, 200240, People's Republic of China.
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