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Huang Z, Zhou RR. Mechanism for FXR to regulate bile acid and glycolipid metabolism to improve NAFLD. Shijie Huaren Xiaohua Zazhi 2023; 31:797-807. [DOI: 10.11569/wcjd.v31.i19.797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/16/2023] [Accepted: 09/21/2023] [Indexed: 10/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease, with liver metabolic disorders as major pathological changes, manifested as abnormal lipid accumulation, liver cell oxidative stress, etc., but its etiology is still unclear. The farnesol X receptor (FXR) is a major bile acid receptor in the "gut-liver axis", via which FXR regulates metabolism and affects the pathophysiological status of various substances through different pathways, thus contributing to the occurrence and development of NAFLD. Therefore, FXR has become a potential therapeutic target for NAFLD. This article reviews the relationship between FXR regulation of bile acid, glucose, and lipid metabolism through the "gut-liver axis" and the occurrence and development of NAFLD, to provide new insights and clues for further research about FXR-based pharmaceutical treatments.
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Affiliation(s)
- Zhi Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Rong-Rong Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
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Li H, Yu XH, Ou X, Ouyang XP, Tang CK. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog Lipid Res 2021; 83:101109. [PMID: 34097928 DOI: 10.1016/j.plipres.2021.101109] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.
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Affiliation(s)
- Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China
| | - Xiang Ou
- Department of Endocrinology, the First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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Effect of Phosphatidylcholine Nanosomes on Phospholipid Composition of the Plasma Membranes in Liver Cells and Blood Serum in Experimental Atherosclerosis. Bull Exp Biol Med 2020; 170:181-184. [PMID: 33263842 DOI: 10.1007/s10517-020-05028-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Indexed: 10/22/2022]
Abstract
Alimentary atherosclerosis is associated with a significant decrease in the content of phosphatidylcholine, the phospholipid that provides antioxidant protection, in the plasma membrane of liver cells, while the level of phosphatidic acid that initiates generation of superoxides, on the contrary, increases. The level of membrane phosphatidylserine, a target of the scavenger receptors, which initiates removal of damaged cells and modified lipoproteins from the circulation was also elevated. In the blood serum of rabbits receiving an atherogenic diet, the content of cardiolipin involved in the immune mechanisms of atherosclerosis development and a risk factor for thrombosis, sharply increased. The level of lysophosphatidylcholine that mediates initiation and progression of atherosclerosis increased. The content of phosphatidylinositol that is involved in the mechanisms protecting from exposure to excess cholesterol was significantly reduced. Treatment of alimentary atherosclerosis with "empty" phosphatidylcholine nanosomes eliminates the key factors initiating atherosclerosis development.
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Calpe B, Kovacs WJ. High-throughput screening in multicellular spheroids for target discovery in the tumor microenvironment. Expert Opin Drug Discov 2020; 15:955-967. [PMID: 32364413 DOI: 10.1080/17460441.2020.1756769] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Solid tumors are highly influenced by a complex tumor microenvironment (TME) that cannot be modeled with conventional two-dimensional (2D) cell culture. In addition, monolayer culture conditions tend to induce undesirable molecular and phenotypic cellular changes. The discrepancy between in vitro and in vivo is an important factor accounting for the high failure rate in drug development. Three-dimensional (3D) multicellular tumor spheroids (MTS) more closely resemble the in vivo situation in avascularized tumors. AREAS COVERED This review describes the use of MTS for anti-cancer drug discovery, with an emphasis on high-throughput screening (HTS) compatible assays. In particular, we focus on how these assays can be used for target discovery in the context of the TME. EXPERT OPINION Arrayed MTS in microtiter plates are HTS compatible but remain more expensive and time consuming than their 2D culture counterpart. It is therefore imperative to use assays with multiplexed readouts, in order to maximize the information that can be gained with the screen. In this context, high-content screening allowing to uncover microenvironmental dependencies is the true added value of MTS-based screening compared to 2D culture-based screening. Hit translation in animal models will, however, be key to allow a broader use of MTS-based screening in industry.
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Affiliation(s)
- Blaise Calpe
- Institute of Molecular Health Sciences, ETH Zurich , Zurich, Switzerland.,Department of Biology, Debiopharm , Lausanne, Switzerland
| | - Werner J Kovacs
- Institute of Molecular Health Sciences, ETH Zurich , Zurich, Switzerland
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Messner S, Fredriksson L, Lauschke VM, Roessger K, Escher C, Bober M, Kelm JM, Ingelman-Sundberg M, Moritz W. Transcriptomic, Proteomic, and Functional Long-Term Characterization of Multicellular Three-Dimensional Human Liver Microtissues. APPLIED IN VITRO TOXICOLOGY 2018; 4:1-12. [PMID: 32953943 PMCID: PMC7500040 DOI: 10.1089/aivt.2017.0022] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Three-Dimensional (3D) liver microtissues, specifically prepared from primary human hepatocytes (PHH) in coculture with nonparenchymal cells (NPCs), have been shown to be a valuable tool for in vitro toxicology. However, a lack of thorough characterization on a functional, transcriptomic, and proteomic level of such models during long-term cultivation is evident. By integrating multiple omics technologies, we provide in this study an in-depth long-term characterization of 3D microtissues composed of PHH from three different donors cocultured with primary NPCs. The 3D human liver microtissues (hLiMTs) exhibited stable adenosine triphosphate (ATP) content and albumin secretion over 5 weeks. Histological analysis indicated a healthy liver tissue with polarized expression of bile salt export pump (BSEP) and multidrug resistance protein 2 (MRP2) in a structure reminiscent of bile canaliculi. The 3D microtissues exhibited stable basal and inducible cytochrome P450 activities up to 5 weeks in culture. Analysis of 40,716 transcripts using RNA arrays revealed distinct similarities to native human liver gene expression. Long-term culture showed a stable phenotype up to 5 weeks, with differences in liver gene expression primarily attributed to individual donors. Proteomic profiling of 2200 unique proteins by label-free LC-MS/MS revealed a relatively stable protein expression where only 7.3% were up- or downregulated more than twofold from day 7 to 35 in culture. Taken together, these results suggest that hLiMTs represent a responsive and physiologically relevant in vitro liver model that maintains stable function over 5 weeks and is therefore well suited for repeated-dose toxicity testing.
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Affiliation(s)
| | - Lisa Fredriksson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M. Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Schmölz L, Birringer M, Lorkowski S, Wallert M. Complexity of vitamin E metabolism. World J Biol Chem 2016; 7:14-43. [PMID: 26981194 PMCID: PMC4768118 DOI: 10.4331/wjbc.v7.i1.14] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/25/2015] [Accepted: 01/19/2016] [Indexed: 02/05/2023] Open
Abstract
Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented.
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Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells. Sci Rep 2016; 6:20646. [PMID: 26865459 PMCID: PMC4749959 DOI: 10.1038/srep20646] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 01/07/2016] [Indexed: 02/08/2023] Open
Abstract
Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with β-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes.
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Schörghofer D, Kinslechner K, Preitschopf A, Schütz B, Röhrl C, Hengstschläger M, Stangl H, Mikula M. The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence. Reprod Biol Endocrinol 2015; 13:88. [PMID: 26251134 PMCID: PMC4528807 DOI: 10.1186/s12958-015-0087-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 07/31/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Human prostate cancer represents one of the most frequently diagnosed cancers in men worldwide. Currently, diagnostic methods are insufficient to identify patients at risk for aggressive prostate cancer, which is essential for early treatment. Recent data indicate that elevated cholesterol levels in the plasma are a prerequisite for the progression of prostate cancer. Here, we analyzed clinical prostate cancer samples for the expression of receptors involved in cellular cholesterol uptake. METHODS We screened mRNA microarray files of prostate cancer samples for alterations in the expression levels of cholesterol transporters. Furthermore, we performed immunohistochemistry analysis on human primary prostate cancer tissue sections derived from patients to investigate the correlation of SR-BI with clinicopathological parameters and the mTOR target pS6. RESULTS In contrast to LDLR, we identified SR-BI mRNA and protein expression to be induced in high Gleason grade primary prostate cancers. Histologic analysis of prostate biopsies revealed that 53.6 % of all cancer samples and none of the non-cancer samples showed high SR-BI staining intensity. The disease-free survival time was reduced (P = 0.02) in patients expressing high intra-tumor levels of SR-BI. SR-BI mRNA correlated with HSD17B1 and HSD3B1 and SR-BI protein staining showed correlation with active ribosomal protein S6 (RS = 0.828, P < 0.00001). CONCLUSIONS We identified SR-BI to indicate human prostate cancer formation, suggesting that increased levels of SR-BI may be involved in the generation of a castration-resistant phenotype.
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Affiliation(s)
- David Schörghofer
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Katharina Kinslechner
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Andrea Preitschopf
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Birgit Schütz
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Clemens Röhrl
- Institute of Medical Chemistry, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Markus Hengstschläger
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Herbert Stangl
- Institute of Medical Chemistry, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
| | - Mario Mikula
- Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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The Histochemistry and Cell Biology pandect: the year 2014 in review. Histochem Cell Biol 2015; 143:339-68. [PMID: 25744491 DOI: 10.1007/s00418-015-1313-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2015] [Indexed: 02/07/2023]
Abstract
This review encompasses a brief synopsis of the articles published in 2014 in Histochemistry and Cell Biology. Out of the total of 12 issues published in 2014, two special issues were devoted to "Single-Molecule Super-Resolution Microscopy." The present review is divided into 11 categories, providing an easy format for readers to quickly peruse topics of particular interest to them.
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