|
1
|
Butt E, Günder T, Stürzebecher P, Kowalski I, Schneider P, Buschmann N, Schäfer S, Bender A, Hermanns HM, Zernecke A. Cholesterol uptake in the intestine is regulated by the LASP1-AKT-NPC1L1 signaling pathway. Am J Physiol Gastrointest Liver Physiol 2024; 327:G25-G35. [PMID: 38713618 DOI: 10.1152/ajpgi.00222.2023] [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: 10/09/2023] [Revised: 04/16/2024] [Accepted: 04/26/2024] [Indexed: 05/09/2024]
Abstract
Cholesterol is essential for the stability and architecture of the plasma membrane and a precursor of bile acids and steroid hormones in mammals. Excess dietary cholesterol uptake leads to hypercholesterolemia and atherosclerosis and plays a role in cancer development. The role of actin-binding scaffolding protein LIM and SH3 protein 1 (LASP1) in cholesterol trafficking has not been investigated previously. Cholesterol levels, its uptake, and excretion were studied in mice deficient for low-density lipoprotein receptor and Lasp1 (Ldlr-/-Lasp1-/- mice) upon feeding a high-fat diet, and in LASP1-knockdown, differentiated human intestinal epithelial CaCo-2 cells. When compared with diet-fed Ldlr-/- control mice, Ldlr-/-Lasp1-/- mice displayed a reduction in serum cholesterol levels. Mechanistically, we identified a new role of LASP1 in controlling the translocation of the intestinal cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) to the apical cell surface, which was limited in LASP1-knockdown human CaCo-2 enterocytes and in the intestine of Ldlr-/- Lasp1-/- compared with Ldlr-/- mice, linked to LASP1-pAKT signaling but not CDC42 activation. In line, a reduction in cholesterol reabsorption was noted in LASP1-knockdown CaCo-2 cells in vitro, and an enhanced cholesterol excretion via the feces was observed in Ldlr-/- Lasp1-/- mice. These data uncover a novel function of Lasp1 in cholesterol trafficking, promoting cholesterol reabsorption in the intestine. Targeting LASP1 locally could thus represent a novel targeting strategy to ameliorate hypercholesterolemia and associated diseases.NEW & NOTEWORTHY We here uncovered LASP1 as a novel regulator of the shuttling of the sterol transporter NPC1L1 to the cell surface in enterocytes to control cholesterol absorption. Accordingly, LASP1-deficient mice displayed lowered serum cholesterol levels under dietary cholesterol supplementation.
Collapse
Affiliation(s)
- Elke Butt
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Thorsten Günder
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Paulina Stürzebecher
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Isabel Kowalski
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Pia Schneider
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Nils Buschmann
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Sarah Schäfer
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Alicia Bender
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Heike M Hermanns
- Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| |
Collapse
|
|
2
|
Zhang L, Shi Y, Liang B, Li X. An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD. Hepatol Commun 2024; 8:e0434. [PMID: 38696365 PMCID: PMC11068152 DOI: 10.1097/hc9.0000000000000434] [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: 02/01/2024] [Accepted: 03/05/2024] [Indexed: 05/04/2024] Open
Abstract
Cholesterol is an essential lipid molecule in mammalian cells. It is not only involved in the formation of cell membranes but also serves as a raw material for the synthesis of bile acids, vitamin D, and steroid hormones. Additionally, it acts as a covalent modifier of proteins and plays a crucial role in numerous life processes. Generally, the metabolic processes of cholesterol absorption, synthesis, conversion, and efflux are strictly regulated. Excessive accumulation of cholesterol in the body is a risk factor for metabolic diseases such as cardiovascular disease, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we first provide an overview of the discovery of cholesterol and the fundamental process of cholesterol metabolism. We then summarize the relationship between dietary cholesterol intake and the risk of developing MASLD, and also the animal models of MASLD specifically established with a cholesterol-containing diet. In the end, the role of cholesterol-induced inflammation in the initiation and development of MASLD is discussed.
Collapse
Affiliation(s)
- Linqiang Zhang
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Yongqiong Shi
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Bin Liang
- Center for Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, School of Life Sciences, Yunnan University, Kunming, Yunnan, China
| | - Xi Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
3
|
Liang B, Wu Q, Wang Y, Shi Y, Sun F, Huang Q, Li G, Liu Y, Zhang S, Xu X, Yao G, Peng J, Zhai X, Wu J, Tan Y, Wu Z, Zhou R, Li S, Wu J, Yang M, Liao W, Shi M. Cdc42-driven endosomal cholesterol transport promotes collateral resistance in HER2-positive gastric cancer. Cancer Lett 2024; 587:216702. [PMID: 38336288 DOI: 10.1016/j.canlet.2024.216702] [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: 09/08/2023] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024]
Abstract
Resistance to trastuzumab and the poor efficacy of subsequent chemotherapy have become major challenges for HER2-positive gastric cancer (GC). As resistance evolves, tumor cells may acquire a new drug susceptibility profile, profoundly impacting the subsequent treatment selection and patient survival. However, the interplay between trastuzumab and other types of drugs in HER2-positive GC remains elusive. In our study, we utilized resistant cell lines and tissue specimens to map the drug susceptibility profile of trastuzumab-resistant GC, discovering that resistance to trastuzumab induces collateral resistance to commonly used chemotherapeutic agents. Additionally, patients with collateral resistance distinguished by a 13-gene scoring model in HER2-positive GC cohorts are predicted to have a poor prognosis and may be sensitive to cholesterol-lowering drugs. Mechanistically, endosomal cholesterol transport is further confirmed to enrich cholesterol in the plasma membrane, contributing to collateral resistance through the Hedgehog-ABCB1 axis. As a driver for cholesterol, Cdc42 is activated by the formation of the NPC1-TβRI-Cdc42 complex to facilitate endosomal cholesterol transport. We demonstrated that inhibiting Cdc42 activation with ZCL278 reduces cholesterol levels in the plasma membrane and reverses collateral resistance between trastuzumab and chemotherapy in vitro and in vivo. Collectively, our findings verify the phenomena and mechanism of collateral resistance between trastuzumab and chemotherapy, and propose a potential therapeutic target and strategy in the second-line treatment for trastuzumab-resistant HER2-positive GC.
Collapse
Affiliation(s)
- Bishan Liang
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Qijing Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Yawen Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Fei Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Qiong Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Guanjun Li
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Yajing Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510060, Guangzhou, China
| | - Shuyi Zhang
- Department of Oncology, Huizhou Municipal Central Hospital, 516008, Huizhou, Guangdong, China
| | - Xin Xu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Guangyu Yao
- Department of General Surgery, Breast Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Jianjun Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 510060, Guangzhou, Guangdong, China
| | - Xiaohui Zhai
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, Guangdong, China
| | - Jing Wu
- Department of Oncology, The People's Hospital of Foshan, 528010, Foshan, Guangdong, China
| | - Yujing Tan
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, Guangdong, China
| | - Zhenzhen Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Rui Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Shaowei Li
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Jianhua Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 271016, Jinan, Shandong, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
| |
Collapse
|
|
4
|
Wang S, Link F, Han M, Chaudhary R, Asimakopoulos A, Liebe R, Yao Y, Hammad S, Dropmann A, Krizanac M, Rubie C, Feiner LK, Glanemann M, Ebert MPA, Weiskirchen R, Henis YI, Ehrlich M, Dooley S. The Interplay of TGF-β1 and Cholesterol Orchestrating Hepatocyte Cell Fate, EMT, and Signals for HSC Activation. Cell Mol Gastroenterol Hepatol 2023; 17:567-587. [PMID: 38154598 PMCID: PMC10883985 DOI: 10.1016/j.jcmgh.2023.12.012] [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: 08/22/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND & AIMS Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. However, the reciprocal regulation of TGF-β1 signaling and cholesterol metabolism in MASLD is yet unknown. METHODS Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA sequencing of murine hepatocyte cell line (alpha mouse liver 12/AML12) and mouse primary hepatocytes treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment [CE] or cholesterol depletion [CD]), and on mice injected with adenovirus-associated virus 8-control/TGF-β1. RESULTS TGF-β1 inhibited messenger RNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, mouse primary hepatocytes, and adenovirus-associated virus-TGF-β1-treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue also were reduced upon TGF-β1 treatment. Smad2/3 phosphorylation after 2 hours of TGF-β1 treatment persisted after CE or CD and was mildly increased after CD, whereas TGF-β1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 hours of incubation with TGF-β1, including epithelial-mesenchymal transition, actin polymerization, and apoptosis. CD mimicked the outcome of long-term TGF-β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. In addition, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells. CONCLUSIONS TGF-β1 inhibits cholesterol metabolism whereas cholesterol attenuates TGF-β1 downstream effects in hepatocytes.
Collapse
Affiliation(s)
- Sai Wang
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Frederik Link
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Mei Han
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Internal Medicine, The Second Hospital of Dalian Medical University, Dalian, China
| | - Roohi Chaudhary
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Anastasia Asimakopoulos
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany
| | - Roman Liebe
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, Magdeburg, Germany
| | - Ye Yao
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Seddik Hammad
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anne Dropmann
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Marinela Krizanac
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany
| | - Claudia Rubie
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Laura Kim Feiner
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias Glanemann
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias P A Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, Aachen, Germany
| | - Yoav I Henis
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Marcelo Ehrlich
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Steven Dooley
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| |
Collapse
|
|
5
|
Aow J, Huang TR, Goh YT, Sun AX, Thinakaran G, Koo EH. Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment. Cell Rep 2023; 42:112774. [PMID: 37450368 PMCID: PMC10449584 DOI: 10.1016/j.celrep.2023.112774] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/08/2023] [Accepted: 06/25/2023] [Indexed: 07/18/2023] Open
Abstract
Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Aβ production and secretion.
Collapse
Affiliation(s)
- Jonathan Aow
- Genome Institute of Singapore, Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Tzu-Rung Huang
- Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - Yeek Teck Goh
- Genome Institute of Singapore, Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore
| | - Alfred Xuyang Sun
- Duke-NUS Graduate Medical School, Signature Research Program in Neuroscience and Behavioural Disorders, Singapore, Singapore
| | - Gopal Thinakaran
- USF Health Byrd Alzheimer's Center and Research Institute and Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
| | - Edward H Koo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Neurosciences, University of California San Diego, San Diego, CA, USA; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
6
|
Wu X, Ma XH, Lin J, Yang X, Shi JH, Xie Z, Chen YX, Zhang WJ. Fluorescent visualization and evaluation of NPC1L1-mediated vesicular endocytosis during intestinal cholesterol absorption in mice. LIFE METABOLISM 2023; 2:load011. [PMID: 39872735 PMCID: PMC11749127 DOI: 10.1093/lifemeta/load011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 01/30/2025]
Abstract
Excessive cholesterol absorption from intestinal lumen contributes to the pathogenesis of hypercholesterolemia, which is an independent risk factor for atherosclerotic cardiovascular disease. Niemann-Pick C1-like 1 (NPC1L1) is a major membrane protein responsible for cholesterol absorption, in which the physiological role of vesicular endocytosis is still controversial, and it lacks a feasible tool to visualize and evaluate the endocytosis of NPC1L1 vesicles in vivo. Here, we genetically labeled endogenous NPC1L1 protein with EGFP in a knock-in mouse model, and demonstrated fluorescent visualization and evaluation of the endocytic vesicles of NPC1L1-cago during intestinal cholesterol absorption. The homozygous NPC1L1-EGFP mice have normal NPC1L1 expression pattern as well as cholesterol homeostasis on chow or high-cholesterol diets. The fluorescence of NPC1L1-EGFP fusion protein localizes at the brush border membrane of small intestine, and EGFP-positive vesicles is visualized beneath the membrane as early as 5 min post oral gavage of cholesterol. Of note, the vesicles colocalize with the early endosomal marker early endosome antigen 1 (EEA1) and the filipin-stained free cholesterol. Pretreatment with NPC1L1 inhibitor ezetimibe inhibits the formation of these cholesterol-induced endocytic vesicles. Our data support the notion that NPC1L1-mediated cholesterol absorption is a vesicular endocytic process. NPC1L1-EGFP mice are a useful model for visualizing cellular NPC1L1-cargo vesicle itineraries and for evaluating NPC1L1 activity in vivo in response to diverse pharmacological agents and nutrients.
Collapse
Affiliation(s)
- Xiaojing Wu
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xian-Hua Ma
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Jie Lin
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Xiaohang Yang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Jian-Hui Shi
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Zhifang Xie
- Ministry of Education Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Weiping J Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| |
Collapse
|
|
7
|
Luo J, Wang JK, Song BL. Lowering low-density lipoprotein cholesterol: from mechanisms to therapies. LIFE METABOLISM 2022; 1:25-38. [PMID: 39872686 PMCID: PMC11749099 DOI: 10.1093/lifemeta/loac004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/31/2022] [Accepted: 05/13/2022] [Indexed: 01/30/2025]
Abstract
Low-density lipoprotein (LDL) is the main carrier of cholesterol and cholesteryl ester in circulation. High plasma levels of LDL cholesterol (LDL-C) are a major risk factor of atherosclerotic cardiovascular disease (ASCVD). LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD. Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy. Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments. Here, we review the most recent advances on LDL-C-lowering drugs, focusing on the mechanisms by which they act to reduce LDL-C levels. The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD. Special treatments for those with little or no LDL receptor function then follow. The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein, which are recently approved and still under investigation for LDL-C lowering, respectively, are also included. Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.
Collapse
Affiliation(s)
- Jie Luo
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Jin-Kai Wang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Bao-Liang Song
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| |
Collapse
|
|
8
|
Xi Y, Yani Z, Jing M, Yinhang W, Xiaohui H, Jing Z, Quan Q, Shuwen H. Mechanisms of induction of tumors by cholesterol and potential therapeutic prospects. Biomed Pharmacother 2021; 144:112277. [PMID: 34624674 DOI: 10.1016/j.biopha.2021.112277] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence suggested that cholesterol is an important integrant of cell membranes, that plays a key role in tumor progression, immune dysregulation, and pathological changes in epigenetic mechanisms. Based on these theories, there is a growing interest on targeting cholesterol in the treatment of cancer. Here, we comprehensively reviewed the major function of cholesterol on oncogenicity, the therapeutic targets of cholesterol and its metabolites in cancer, and provide detailed insight into the essential roles of cholesterol in mediating immune and epigenetic mechanisms of the tumor microenvironment. It is also worth mentioning that the gut microbiome is an indispensable component of cancer mediation because of its role in cholesterol metabolism. Finally, we summarized recent studies on the potential targets of cholesterol and their metabolism, to provide more therapeutic interventions in oncology.
Collapse
Affiliation(s)
- Yang Xi
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang 313000, China.
| | - Zhou Yani
- Graduate School of Medical College of Zhejiang University, No. 268 Kaixuan Road, Jianggan District, Hangzhou, Zhejiang 310029, China.
| | - Mao Jing
- Graduate School of Medical College of Zhejiang University, No. 268 Kaixuan Road, Jianggan District, Hangzhou, Zhejiang 310029, China.
| | - Wu Yinhang
- Graduate School of Second Clinical Medicine Faculty, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China.
| | - Hou Xiaohui
- Graduate School of Nursing, Huzhou University, No. 1 Bachelor Road, Wuxing District, Huzhou, Zhejiang 313000, China.
| | - Zhuang Jing
- Department of Nursing, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang 313000, China.
| | - Qi Quan
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang 313000, China.
| | - Han Shuwen
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang 313000, China.
| |
Collapse
|
|
9
|
Colardo M, Martella N, Pensabene D, Siteni S, Di Bartolomeo S, Pallottini V, Segatto M. Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis. Int J Mol Sci 2021; 22:5692. [PMID: 34073639 PMCID: PMC8198482 DOI: 10.3390/ijms22115692] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/14/2022] Open
Abstract
Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins' signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.
Collapse
Affiliation(s)
- Mayra Colardo
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Noemi Martella
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Daniele Pensabene
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Silvia Siteni
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Sabrina Di Bartolomeo
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Valentina Pallottini
- Department of Science, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy;
- Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano 64, 00143 Rome, Italy
| | - Marco Segatto
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| |
Collapse
|
|
10
|
Vona R, Iessi E, Matarrese P. Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity? Front Cell Dev Biol 2021; 9:622908. [PMID: 33816471 PMCID: PMC8017202 DOI: 10.3389/fcell.2021.622908] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
Collapse
Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Elisabetta Iessi
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| |
Collapse
|
|
11
|
Nakano T, Inoue I, Takenaka Y, Ito R, Kotani N, Sato S, Nakano Y, Hirasaki M, Shimada A, Murakoshi T. Ezetimibe impairs transcellular lipid trafficking and induces large lipid droplet formation in intestinal absorptive epithelial cells. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158808. [PMID: 32860884 DOI: 10.1016/j.bbalip.2020.158808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 07/30/2020] [Accepted: 08/18/2020] [Indexed: 01/26/2023]
Abstract
Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein, which mediates intracellular cholesterol trafficking from the brush border membrane to the endoplasmic reticulum, where chylomicron assembly takes place in enterocytes or in the intestinal absorptive epithelial cells. Cholesterol is a minor lipid constituent of chylomicrons; however, whether or not a shortage of cholesterol attenuates chylomicron assembly is unknown. The aim of this study was to examine the effect of ezetimibe, a potent NPC1L1 inhibitor, on trans-epithelial lipid transport, and chylomicron assembly and secretion in enterocytes. Caco-2 cells, an absorptive epithelial model, grown onto culture inserts were given lipid micelles from the apical side, and chylomicron-like triacylglycerol-rich lipoprotein secreted basolaterally were analyzed after a 24-h incubation period in the presence of ezetimibe up to 50 μM. The secretion of lipoprotein and apolipoprotein B48 were reduced by adding ezetimibe (30% and 34%, respectively). Although ezetimibe allowed the cells to take up cholesterol normally, the esterification was abolished. Meanwhile, oleic acid esterification was unaffected. Moreover, ezetimibe activated sterol regulatory element-binding protein 2 by approximately 1.5-fold. These results suggest that ezetimibe limited cellular cholesterol mobilization required for lipoprotein assembly. In such conditions, large lipid droplet formation in Caco-2 cells and the enterocytes of mice were induced, implying that unprocessed triacylglycerol was sheltered in these compartments. Although ezetimibe did not reduce the post-prandial lipid surge appreciably in triolein-infused mice, the results of the present study indicated that pharmacological actions of ezetimibe may participate in a novel regulatory mechanism for the efficient chylomicron assembly and secretion.
Collapse
Affiliation(s)
- Takanari Nakano
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
| | - Ikuo Inoue
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yasuhiro Takenaka
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan; Department of Physiology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Rina Ito
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Norihiro Kotani
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Sawako Sato
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yuka Nakano
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Masataka Hirasaki
- Division of Developmental Biology, Research Center for Genomic Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Akira Shimada
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Takayuki Murakoshi
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| |
Collapse
|
|
12
|
Kishimoto T, Tomishige N, Murate M, Ishitsuka R, Schaller H, Mély Y, Ueda K, Kobayashi T. Cholesterol asymmetry at the tip of filopodia during cell adhesion. FASEB J 2020; 34:6185-6197. [PMID: 32162745 DOI: 10.1096/fj.201900065rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/26/2020] [Accepted: 02/26/2020] [Indexed: 12/28/2022]
Abstract
During adhesion, cells develop filopodia to facilitate the attachment to the extracellular matrix. The small guanosine triphosphate (GTP)-binding protein, Cdc42, plays a central role in the formation of filopodia. It has been reported that Cdc42 activity is regulated by cholesterol (Chol). We examined Chol distribution in filopodia using Chol-binding domain 4 (D4) fragment of bacterial toxin, perfringolysin O that senses high membrane concentration of Chol. Our results indicate that fluorescent D4 was enriched at the tip of the outer leaflet of filopodia in the initiation phase of cell adhesion. This enrichment was accompanied by a defect of D4 labeling in the inner leaflet. Steady phase adhered cell experiment indicated that both Cdc42 and ATP-binding cassette transporter, ABCA1, were involved in the binding of D4 to the cell surface. Depletion of Chol activated Cdc42. Our results suggest that asymmetric distribution of Chol at the tip of filopodia induces activation of Cdc42, and thus, facilitates filopodia formation.
Collapse
Affiliation(s)
- Takuma Kishimoto
- Lipid Biology Laboratory, RIKEN, Saitama, Japan.,Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University Graduate School of Life Science, Sapporo, Japan
| | - Nario Tomishige
- Lipid Biology Laboratory, RIKEN, Saitama, Japan.,UMR 7021 CNRS, Université de Strasbourg, Illkirch, France
| | - Motohide Murate
- Lipid Biology Laboratory, RIKEN, Saitama, Japan.,UMR 7021 CNRS, Université de Strasbourg, Illkirch, France
| | | | - Hubert Schaller
- Institut de Biologie Moléculaire des Plantes, UPR 2357, CNRS, Université de Strasbourg, Strasbourg, France
| | - Yves Mély
- UMR 7021 CNRS, Université de Strasbourg, Illkirch, France
| | - Kazumitsu Ueda
- Division of Applied Life Sciences, Graduate School of Agriculture, Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
| | - Toshihide Kobayashi
- Lipid Biology Laboratory, RIKEN, Saitama, Japan.,UMR 7021 CNRS, Université de Strasbourg, Illkirch, France
| |
Collapse
|
|
13
|
Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol 2019; 21:225-245. [DOI: 10.1038/s41580-019-0190-7] [Citation(s) in RCA: 450] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2019] [Indexed: 12/14/2022]
|
|
14
|
Chen L, Chen XW, Huang X, Song BL, Wang Y, Wang Y. Regulation of glucose and lipid metabolism in health and disease. SCIENCE CHINA-LIFE SCIENCES 2019; 62:1420-1458. [PMID: 31686320 DOI: 10.1007/s11427-019-1563-3] [Citation(s) in RCA: 164] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/15/2019] [Indexed: 02/08/2023]
Abstract
Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of glucose, fatty acids and cholesterol are often intertwined and regulated. For example, glucose can be converted to fatty acids and cholesterol through de novo lipid biosynthesis pathways. Excessive lipids are secreted in lipoproteins or stored in lipid droplets. The metabolites of glucose and lipids are dynamically transported intercellularly and intracellularly, and then converted to other molecules in specific compartments. The disorders of glucose and lipid metabolism result in severe diseases including cardiovascular disease, diabetes and fatty liver. This review summarizes the major metabolic aspects of glucose and lipid, and their regulations in the context of physiology and diseases.
Collapse
Affiliation(s)
- Ligong Chen
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China.
| | - Xiao-Wei Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
| | - Xun Huang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Bao-Liang Song
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
| | - Yan Wang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
| | - Yiguo Wang
- MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| |
Collapse
|
|
15
|
Nakano T, Inoue I, Murakoshi T. A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels. Nutrients 2019; 11:nu11020310. [PMID: 30717222 PMCID: PMC6412963 DOI: 10.3390/nu11020310] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 12/27/2022] Open
Abstract
Cholesterol homeostasis is maintained through a balance of de novo synthesis, intestinal absorption, and excretion from the gut. The small intestine contributes to cholesterol homeostasis by absorbing and excreting it, the latter of which is referred to as trans-intestinal cholesterol efflux (TICE). Because the excretion efficiency of endogenous cholesterol is inversely associated with the development of atherosclerosis, TICE provides an attractive therapeutic target. Thus, elucidation of the mechanism is warranted. We have shown that intestinal cholesterol absorption and TICE are inversely correlated in intestinal perfusion experiments in mice. In this review, we summarized 28 paired data sets for absorption efficiency and fecal neutral sterol excretion, a surrogate marker of TICE, obtained from 13 available publications in a figure, demonstrating the inverse correlation were nearly consistent with the assumption. We then offer a bidirectional flux model that accommodates absorption and TICE occurring in the same segment. In this model, the brush border membrane (BBM) of intestinal epithelial cells stands as the dividing ridge for cholesterol fluxes, making the opposite fluxes competitive and being coordinated by shared BBM-localized transporters, ATP-binding cassette G5/G8 and Niemann-Pick C1-like 1. Furthermore, the idea is applied to address how excess plant sterol/stanol (PS) intake reduces circulating cholesterol level, because the mechanism is still unclear. We propose that unabsorbable PS repeatedly shuttles between the BBM and lumen and promotes concomitant cholesterol efflux. Additionally, PSs, which are chemically analogous to cholesterol, may disturb the trafficking machineries that transport cholesterol to the cell interior.
Collapse
Affiliation(s)
- Takanari Nakano
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
| | - Ikuo Inoue
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
| | - Takayuki Murakoshi
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
| |
Collapse
|
|
16
|
Zhang YY, Fu ZY, Wei J, Qi W, Baituola G, Luo J, Meng YJ, Guo SY, Yin H, Jiang SY, Li YF, Miao HH, Liu Y, Wang Y, Li BL, Ma YT, Song BL. A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science 2018; 360:1087-1092. [DOI: 10.1126/science.aao6575] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 02/07/2018] [Accepted: 04/17/2018] [Indexed: 12/19/2022]
Abstract
A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1-deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.
Collapse
|
|
17
|
Regulated Entry of Hepatitis C Virus into Hepatocytes. Viruses 2017; 9:v9050100. [PMID: 28486435 PMCID: PMC5454413 DOI: 10.3390/v9050100] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 04/24/2017] [Accepted: 05/02/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a model for the study of virus–host interaction and host cell responses to infection. Virus entry into hepatocytes is the first step in the HCV life cycle, and this process requires multiple receptors working together. The scavenger receptor class B type I (SR-BI) and claudin-1 (CLDN1), together with human cluster of differentiation (CD) 81 and occludin (OCLN), constitute the minimal set of HCV entry receptors. Nevertheless, HCV entry is a complex process involving multiple host signaling pathways that form a systematic regulatory network; this network is centrally controlled by upstream regulators epidermal growth factor receptor (EGFR) and transforming growth factor β receptor (TGFβ-R). Further feedback regulation and cell-to-cell spread of the virus contribute to the chronic maintenance of HCV infection. A comprehensive and accurate disclosure of this critical process should provide insights into the viral entry mechanism, and offer new strategies for treatment regimens and targets for HCV therapeutics.
Collapse
|
|
18
|
Nghiem-Rao TH, Patel SB. Investigating Sitosterolemia to Understand Lipid Physiology. ACTA ACUST UNITED AC 2017; 8:649-658. [PMID: 29928317 DOI: 10.2217/clp.13.60] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The cholesterol molecule is at the center of the pathophysiology of many vascular diseases. Whole-body cholesterol pools are maintained by a balance of endogenous synthesis, dietary absorption and elimination from our bodies. While the cellular aspects of cholesterol metabolism received significant impetus from the seminal work of Goldstein and Brown investigating LDL receptor trafficking, how dietary cholesterol was absorbed and eliminated was relatively neglected. The identification of the molecular defect a rare human disorder, Sitosterolemia, led to elucidation of a key mechanism of how we regulate the excretory pathway in the liver and in the intestine. Two proteins, ABCG5 and ABCG8, constitute a heterodimeric transporter that facilitates the extrusion of sterols from the cell into the biliary lumen, with a preference for xenosterols. This mechanism explained how dietary xenosterols are prevented from accumulating in our bodies. In addition, this disease has also highlighted the potential harm of xenosterols; macrothrombocytopenia, liver disease and endocrine disruption are seen when xenosterols accumulate. Mouse models of this disease suggest that there are more dramatic alterations of physiology, suggesting that these highly conserved mechanisms have evolved to prevent these xenosterols from accumulating in our bodies.
Collapse
Affiliation(s)
| | - Shailendra B Patel
- Medical College of Wisconsin, and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI
| |
Collapse
|
|
19
|
Wüstner D, Solanko K. How cholesterol interacts with proteins and lipids during its intracellular transport. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015; 1848:1908-26. [DOI: 10.1016/j.bbamem.2015.05.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 04/14/2015] [Accepted: 05/13/2015] [Indexed: 12/13/2022]
|
|
20
|
Tomkin GH, Owens D. Dyslipidaemia of diabetes and the intestine. World J Diabetes 2015; 6:970-977. [PMID: 26185604 PMCID: PMC4499530 DOI: 10.4239/wjd.v6.i7.970] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 01/06/2015] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care. In particular the economic burden is growing at an alarming rate in parallel with the increasing world-wide prevalence of diabetes. The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism. Raised triglycerides being the hallmark of uncontrolled diabetes, i.e., in the presence of hyperglycaemia. The explosion of type 2 diabetes has generated increasing interest on the aetiology of atherosclerosis in diabetic patients. The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years. In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine. Recent evidence has secured the chylomicron as a major player in the atherogenic process. In diabetes chylomicron production is increased through disturbance in cholesterol absorption, in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase. ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia. The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein. The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.
Collapse
|
|
21
|
Kurano M, Hara M, Satoh H, Tsukamoto K. Hepatic NPC1L1 overexpression ameliorates glucose metabolism in diabetic mice via suppression of gluconeogenesis. Metabolism 2015; 64:588-96. [PMID: 25660144 DOI: 10.1016/j.metabol.2015.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 12/27/2014] [Accepted: 01/21/2015] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Inhibition of intestinal NPC1L1 by ezetimibe has been demonstrated to improve glucose metabolism in rodent models; however, the role of hepatic NPC1L1 in glucose metabolism has not been elucidated. In this study, we analyzed the effects of hepatic NPC1L1 on glucose metabolism. MATERIAL AND METHODS We overexpressed NPC1L1 in the livers of lean wild type mice, diet-induced obesity mice and db/db mice with adenoviral gene transfer. RESULTS We found that in all three mouse models, hepatic NPC1L1 overexpression lowered fasting blood glucose levels as well as blood glucose levels on ad libitum; in db/db mice, hepatic NPC1L1 overexpression improved blood glucose levels to almost the same as those found in lean wild type mice. A pyruvate tolerance test revealed that gluconeogenesis was suppressed by hepatic NPC1L1 overexpression. Further analyses revealed that hepatic NPC1L1 overexpression decreased the expression of FoxO1, resulting in the reduced expression of G6Pase and PEPCK, key enzymes in gluconeogenesis. CONCLUSIONS These results indicate that hepatic NPC1L1 might have distinct properties of suppressing gluconeogenesis via inhibition of FoxO1 pathways.
Collapse
Affiliation(s)
- Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, University of Tokyo, Japan.
| | - Masumi Hara
- Department of Internal Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan.
| | - Hiroaki Satoh
- Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan.
| | - Kazuhisa Tsukamoto
- Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan.
| |
Collapse
|
|
22
|
Brachet A, Norwood S, Brouwers JF, Palomer E, Helms JB, Dotti CG, Esteban JA. LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery. ACTA ACUST UNITED AC 2015; 208:791-806. [PMID: 25753037 PMCID: PMC4362467 DOI: 10.1083/jcb.201407122] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cholesterol acts as a sensor of NMDA receptor activation and as a trigger of downstream signaling by engaging small GTPase activation and AMPA receptor synaptic delivery during long-term potentiation. Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate–type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP.
Collapse
Affiliation(s)
- Anna Brachet
- Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Stephanie Norwood
- Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Jos F Brouwers
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, Netherlands
| | - Ernest Palomer
- Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - J Bernd Helms
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, Netherlands
| | - Carlos G Dotti
- Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - José A Esteban
- Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| |
Collapse
|
|
23
|
Lee CL, Wen JY, Hsu YW, Pan TM. Monascus-fermented yellow pigments monascin and ankaflavin showed antiobesity effect via the suppression of differentiation and lipogenesis in obese rats fed a high-fat diet. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2013; 61:1493-1500. [PMID: 23360447 DOI: 10.1021/jf304015z] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Monascus-fermented monascin and ankaflavin are found to strongly inhibit differentiation and lipogenesis and stimulate lipolysis effects in a 3T3-L1 preadipocyte model, but the in vivo regulation mechanism is unclear. This study uses obese rats caused by a high-fat diet to examine the effects of daily monascin and ankaflavin feeding (8 weeks) on antiobesity effects and modulation of differentiation, lipogenesis, and lipid absorption. The results show that monascin and ankaflavin had a significant antiobesity effect, which should result from the modulation of monascin and ankaflavin on the inhibition of differentiation by inhibiting CCAT/enhancer-binding protein β (C/EBPβ) expression (36.4% and 48.3%) and its downstream peroxisome proliferator-activated receptor γ (PPARγ) (55.6% and 64.5%) and CCAT/enhancer-binding protein α (C/EBPα) expressions (25.2% and 33.2%) and the inhibition of lipogenesis by increasing lipase activity (14.0% and 10.7%) and decreasing heparin releasable lipoprotein lipase (HR-LPL) activity (34.8% and 30.5%). Furthermore, monascin and ankaflavin are the first agents found to suppress Niemann-Pick C1 Like 1 (NPC1L1) protein expression (73.6% and 26.1%) associated with small intestine tissue lipid absorption. Importantly, monascin and ankaflavin are not like monacolin K, which increases creatine phosphokinase (CPK) activity, known as a rhabdomyolysis indicator.
Collapse
Affiliation(s)
- Chun-Lin Lee
- Department of Life Science, National Taitung University, Taitung, Taiwan, Republic of China
| | | | | | | |
Collapse
|
|
24
|
Hu X, Steffensen KR, Jiang ZY, Parini P, Gustafsson JÅ, Gåfvels M, Eggertsen G. LXRβ activation increases intestinal cholesterol absorption, leading to an atherogenic lipoprotein profile. J Intern Med 2012; 272:452-64. [PMID: 22329358 DOI: 10.1111/j.1365-2796.2012.02529.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVES Liver X receptors (LXRs) are essential for the regulation of intestinal cholesterol absorption. Because two isoforms exist, LXRα and LXRβ, with overlapping but not identical functions, we investigated whether LXRα and LXRβ exert different effects on intestinal cholesterol absorption. DESIGN Wild-type (WT), LXRα(-/-) and LXRβ(-/-) mice were fed control diet, 0.2% cholesterol-enriched diet or 0.2% cholesterol-enriched diet plus the LXR agonist GW3965. RESULTS When fed a control diet, all three genotypes showed similar levels of cholesterol absorption. Of interest, a significant increase in cholesterol absorption was found in the LXRα(-/-) mice, but not in the WT or LXRβ(-/-) animals, when fed a diet enriched with 0.2% cholesterol or 0.2% cholesterol + GW3965. Reduced faecal neutral sterol excretion and a hydrophobic bile acid profile were also observed in LXRα(-/-) mice. Greater increases in the apolipoprotein (apo)B-containing lipoproteins in serum were seen in the LXRα(-/-) mice. A 0.2% cholesterol +GW3965 diet suppressed intestinal Npc1l1 protein expression to the same extent for all genotypes, while Abca1 and Abcg5 were elevated to the same degree. CONCLUSIONS In the intestine, LXRα and LXRβ seem to exert similar effects on expression of cholesterol-transporting proteins such as Npc1l1. Selective activation of LXRβ may generate effects such as increased cholesterol absorption and elevated serum levels of apoB-containing lipoproteins, which seem to be counteracted by LXRα. Therefore, an intestinal LXRβ-specific pathway might exist in terms of cholesterol transportation in addition to the main pathway.
Collapse
Affiliation(s)
- X Hu
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Xie 谢畅 C, Zhou 周章森 ZS, Li 李钠 N, Bian 卞艳 Y, Wang 王永建 YJ, Wang 王丽娟 LJ, Li 李伯良 BL, Song 宋保亮 BL. Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. J Lipid Res 2012; 53:2092-2101. [PMID: 22811412 PMCID: PMC3435542 DOI: 10.1194/jlr.m027359] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 07/05/2012] [Indexed: 11/20/2022] Open
Abstract
The multiple transmembrane protein Niemann-Pick C1 like1 (NPC1L1) is essential for intestinal cholesterol absorption. Ezetimibe binds to NPC1L1 and is a clinically used cholesterol absorption inhibitor. Recent studies in cultured cells have shown that NPC1L1 mediates cholesterol uptake through vesicular endocytosis that can be blocked by ezetimibe. However, how NPC1L1 and ezetimibe work in the small intestine is unknown. In this study, we found that NPC1L1 distributed in enterocytes of villi and transit-amplifying cells of crypts. Acyl-CoA cholesterol acyltransferase 2 (ACAT2), another important protein for cholesterol absorption by providing cholesteryl esters to chylomicrons, was mainly presented in the apical cytoplasm of enterocytes. NPC1L1 and ACAT2 were highly expressed in jejunum and ileum. ACAT1 presented in the Paneth cells of crypts and mesenchymal cells of villi. In the absence of cholesterol, NPC1L1 was localized on the brush border of enterocytes. Dietary cholesterol induced the internalization of NPC1L1 to the subapical layer beneath the brush border and became partially colocalized with the endosome marker Rab11. Ezetimibe blocked the internalization of NPC1L1 and cholesterol and caused their retention in the plasma membrane. This study demonstrates that NPC1L1 mediates cholesterol entering enterocytes through vesicular endocytosis and that ezetimibe blocks this step in vivo.
Collapse
Affiliation(s)
- Chang Xie 谢畅
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhang-Sen Zhou 周章森
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Na Li 李钠
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yan Bian 卞艳
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yong-Jian Wang 王永建
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Li-Juan Wang 王丽娟
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Bo-Liang Li 李伯良
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Bao-Liang Song 宋保亮
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| |
Collapse
|
|
26
|
Howles PN, Hui DY. Physiological role of hepatic NPC1L1 in human cholesterol and lipoprotein metabolism: new perspectives and open questions. J Lipid Res 2012; 53:2253-5. [PMID: 22941774 DOI: 10.1194/jlr.e031823] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Philip N Howles
- Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | | |
Collapse
|
|
27
|
Goh LL, Manser E. The GTPase-deficient Rnd proteins are stabilized by their effectors. J Biol Chem 2012; 287:31311-20. [PMID: 22807448 DOI: 10.1074/jbc.m111.327056] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Rnd proteins are Rho family GTP-binding proteins with cellular functions that antagonize RhoA signaling. We recently described a new Rnd3 effector Syx, also named PLEKHG5, that interacts with Rnds via a Raf1-like "Ras-binding domain." Syx is a multidomain RhoGEF that participates in early zebrafish development. Here we demonstrated that Rnd1, Rnd2, and Rnd3 stability is acutely dependent on interaction with their effectors such as Syx or p190 RhoGAP. Although Rnd3 turnover is blocked by treatment of cells with MG132, we provide evidence that such turnover is mediated indirectly by effects on the Rnd3 effectors, rather than on Rnd3 itself, which is not significantly ubiquitinated. The minimal regions of Syx and p190 RhoGAP that bind Rnd3 are not sequence-related but have similar effects. We have identified features that allow for Rnd3 turnover including a conserved Lys-45 close to the switch I region and the C-terminal membrane-binding domain of Rnd3, which cannot be substituted by the equivalent Cdc42 CAAX sequence. By contrast, an effector binding-defective mutant of Rnd3 when overexpressed undergoes turnover at normal rates. Interestingly the activity of the RhoA-regulated kinase ROCK stimulates Rnd3 turnover. This study suggests that Rnd proteins are regulated through feedback mechanisms in cells where the level of effectors and RhoA activity influence the stability of Rnd proteins. This effector feedback behavior is analogous to the ability of ACK1 and PAK1 to prolong the lifetime of the active GTP-bound state of Cdc42 and Rac1.
Collapse
Affiliation(s)
- Liuh Ling Goh
- Rho GTPases Signaling Group, Institute of Medical Biology, 8A Biomedical Grove, 06-06 Immunos Building 138648, Singapore
| | | |
Collapse
|
|
28
|
Abstract
Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.
Collapse
Affiliation(s)
- Nada A Abumrad
- Center for Human Nutrition and Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | | |
Collapse
|
|
29
|
Niemann-Pick C1-Like 1 and cholesterol uptake. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1821:964-72. [PMID: 22480541 DOI: 10.1016/j.bbalip.2012.03.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Revised: 03/09/2012] [Accepted: 03/12/2012] [Indexed: 01/27/2023]
Abstract
Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein responsible for dietary cholesterol and biliary cholesterol absorption. Consistent with its functions, NPC1L1 distributes on the brush border membrane of enterocytes and the canalicular membrane of hepatocytes in humans. As the molecular target of ezetimibe, a hypocholesterolemic drug, its physiological and pathological significance has been recognized and intensively studied for years. Recently, plenty of new findings reveal the molecular mechanism of NPC1L1's role in cholesterol uptake, which may provide new insights on our understanding of cholesterol absorption. In this review, we summarized recent progress in these studies and proposed a working model, hoping to provide new perspectives on the regulation of cholesterol transport and metabolism.
Collapse
|