FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4313367777> ?p ?o ?g. }

• W4313367777 endingPage "459" @default.
• W4313367777 startingPage "457" @default.
• W4313367777 abstract "Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in miceJournal of HepatologyVol. 78Issue 3PreviewAcetaminophen (APAP) is the most common cause of drug-induced liver injury (DILI); however, treatment options are limited. Mas is a G protein-coupled receptor whose role in APAP-induced hepatotoxicity has not yet been examined. Full-Text PDF Open Access See Article, pages 543–557 See Article, pages 543–557 The renin–angiotensin system (RAS), consists primarily of an enzymatic cascade in which angiotensinogen is converted to angiotensin (Ang) I and subsequently to Ang II by the actions of renin- and angiotensin-converting enzyme, respectively.[1]Giacchetti G. Sechi L.A. Rilli S. Carey R.M. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes.Trends Endocrinol Metab. 2005; 16: 120-126Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Besides Ang II, other Ang peptides such as Ang-(1–7) may also have important biological activities. Ang-(1–7) is derived from Ang I and Ang II and activates the G protein-coupled receptor called Mas, which is widely expressed.[2]Santos R.A. Simoes e Silva A.C. Maric C. Silva D.M. Machado R.P. de Buhr I. et al.Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.Proc Natl Acad Sci U S A. 2003; 100: 8258-8263Crossref PubMed Scopus (1437) Google Scholar The RAS, most well-known for being a potent regulator of blood pressure and hydromineral balance, is also involved in multiple physiological actions, including the regulation of key metabolic pathways, particularly related with glucose homeostasis and fatty acid metabolism. However, the role of the different RAS components is complex since Ang-(1–7) opposes many of the actions of Ang II. In different rodent models the genetic disruption of several RAS components such as renin, ACE, Ang II type 1 receptor and Ang II type 2 receptor results in protection from diet-induced obesity and reduces hepatic steatosis.[3]de Kloet A.D. Krause E.G. Woods S.C. The renin angiotensin system and the metabolic syndrome.Physiol Behav. 2010; 100: 525-534Crossref PubMed Scopus (148) Google Scholar Consequently, increased levels of Ang II have been observed in both patients with obesity and type 2 diabetes.[1]Giacchetti G. Sechi L.A. Rilli S. Carey R.M. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes.Trends Endocrinol Metab. 2005; 16: 120-126Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Conversely, the Ang-(1-7)/Mas axis improves lipid metabolism and prevents diet-induced hepatic steatosis and inflammation in mice.[4]Feltenberger J.D. Andrade J.M. Paraiso A. Barros L.O. Filho A.B. Sinisterra R.D. et al.Oral formulation of angiotensin-(1-7) improves lipid metabolism and prevents high-fat diet-induced hepatic steatosis and inflammation in mice.Hypertension. 2013; 62: 324-330Crossref PubMed Scopus (81) Google Scholar In agreement with this, mice lacking the Mas receptor display increased abdominal fat mass, dyslipidemia, glucose intolerance and reduced insulin sensitivity.[5]Santos S.H. Fernandes L.R. Mario E.G. Ferreira A.V. Porto L.C. Alvarez-Leite J.I. et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism.Diabetes. 2008; 57: 340-347Crossref PubMed Scopus (211) Google Scholar The mechanisms underlying the beneficial effects of Ang-(1-7) involve the activation of the IRS-1/Akt/AMPKα pathway in hepatocytes, which thereby restores hepatic mitochondrial function and glycolipid metabolism in the liver of diet-induced obese mice.[6]Song L.N. Liu J.Y. Shi T.T. Zhang Y.C. Xin Z. Cao X. et al.Angiotensin-(1-7), the product of ACE2 ameliorates NAFLD by acting through its receptor Mas to regulate hepatic mitochondrial function and glycolipid metabolism.FASEB J. 2020; 34: 16291-16306Crossref PubMed Scopus (13) Google Scholar Autophagy, a catabolic process coordinated by a complex network of more than 30 genes and their protein products (autophagy-related genes), is conserved in eukaryotic cells and critical to maintain the cellular energy balance.[7]Singh R. Cuervo A.M. Autophagy in the cellular energetic balance.Cell Metab. 2011; 13: 495-504Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar The term autophagy includes three processes, of which macroautophagy is quantitatively the most important.[8]Allaire M. Rautou P.E. Codogno P. Lotersztajn S. Autophagy in liver diseases: time for translation?.J Hepatol. 2019; 70: 985-998Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Macroautophagy starts with autophagosome formation[9]Singh R. Cuervo A.M. Lipophagy: connecting autophagy and lipid metabolism.Int J Cel Biol. 2012; 282041Crossref PubMed Scopus (343) Google Scholar where, among others, lipid droplets (LDs) may be incorporated. The autophagosome moves to deliver its cargo to the lysosomes for degradation. Lysosomes, traditionally known to degrade lipids from endocytosed lipoproteins due to their high hydrolytic enzymatic capacity, were recognized in 2009 as organelles that can participate in LD breakdown in a process called lipophagy.[10]Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. et al.Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2730) Google Scholar During lipophagy, upregulated during prolonged starvation and in response to lipid overload,[9]Singh R. Cuervo A.M. Lipophagy: connecting autophagy and lipid metabolism.Int J Cel Biol. 2012; 282041Crossref PubMed Scopus (343) Google Scholar,[10]Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. et al.Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2730) Google Scholar there is a certain level of selectivity towards the sequestration of LDs.[10]Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. et al.Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2730) Google Scholar Lysosome lipases hydrolyze cholesteryl esters and triglycerides, releasing fatty acids, which might be channeled to the mitochondrial matrix to be oxidized. Hence, inhibition of autophagy leads to increased intracellular cholesterol and triglyceride storage and reduced rates of fatty acid oxidation (FAO).[10]Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. et al.Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2730) Google Scholar Impaired autophagy induced by numerous signals that contribute to metabolic (dysfunction)-associated fatty liver disease[11]Czaja M.J. Function of autophagy in nonalcoholic fatty liver disease.Dig Dis Sci. 2016; 61: 1304-1313Crossref PubMed Scopus (122) Google Scholar might underlie the development and progression of the disease. Deletion of proteins involved in autophagy in mouse models exacerbates lipid overload,[10]Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. et al.Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2730) Google Scholar,[12]Xiong X. Tao R. DePinho R.A. Dong X.C. The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism.J Biol Chem. 2012; 287: 39107-39114Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar while pharmacological upregulation of autophagy reduces hepatotoxicity and steatosis in alcohol-induced fatty liver.[13]Ding W.X. Li M. Chen X. Ni H.M. Lin C.W. Gao W. et al.Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.Gastroenterology. 2010; 139: 1740-1752Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar Thus, induction of autophagy might be an interesting therapeutic approach in certain liver diseases. Following this line, autophagy also plays a critical role in maintaining liver homeostasis in response to liver injury promoted by hepatotoxic drugs.[8]Allaire M. Rautou P.E. Codogno P. Lotersztajn S. Autophagy in liver diseases: time for translation?.J Hepatol. 2019; 70: 985-998Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar This is the case for acetaminophen (APAP, paracetamol)-induced hepatotoxicity.[14]Ni H.M. Bockus A. Boggess N. Jaeschke H. Ding W.X. Activation of autophagy protects against acetaminophen-induced hepatotoxicity.Hepatology. 2012; 55: 222-232Crossref PubMed Scopus (343) Google Scholar APAP is one of the most commonly used pain relievers and antipyretics; however, it is also responsible for around 500 deaths annually in the US alone, 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year.[15]Lee W.M. Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away?.J Hepatol. 2017; 67: 1324-1331Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar There is an urgent need to find effective antidotes. Mitochondrial dysfunction and damage are a hallmark of APAP-induced cell necrosis. Enhanced autophagy has been shown to remove damaged mitochondria and prevent reactive oxygen species production in this context.[14]Ni H.M. Bockus A. Boggess N. Jaeschke H. Ding W.X. Activation of autophagy protects against acetaminophen-induced hepatotoxicity.Hepatology. 2012; 55: 222-232Crossref PubMed Scopus (343) Google Scholar The hepatoprotective effect of autophagy might be valuable in APAP-induced liver injury. In a detailed study performed in animal models, cellular and human samples, coordinating RNA sequencing, proteomics, metabolomics, lipidomics and metabolic flux analysis, Chen S, Lu Z, Jia H, Yang B et al.[16]Chen S. Lu Z. Jia H. Yang B. Liu C. Yang Y. et al.Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice.J Hepatol. 2023; 78: 543-557Abstract Full Text Full Text PDF Scopus (1) Google Scholar demonstrate evidence for a protective role of Mas activation, specifically in hepatocytes, in APAP overdose. In this study using different transgenic animals, as well as pharmacological treatments, the authors identify that although intrahepatic Mas expression is increased in patients and animal models with drug-induced liver injury, lack of Mas1 worsens APAP-induced hepatotoxicity in mice. In addition, they also found that activation of Mas through the specific pharmacological agent AVE0991, ameliorates APAP-induced hepatotoxicity (intrahepatic inflammation, cell death, mitochondrial stress) through induction of lipophagy, lipolysis and FAO, processes that are impaired in Mas1-deficient animal models. The results show that AVE0991 enhances the breakdown of triglycerides and the in vivo turnover of fatty acids. To confirm the beneficial roles of autophagy and FAO induction in APAP-induced liver injury and to demonstrate that autophagy plays a role upstream of FAO, the authors carry out a series of experiments with autophagy inducers and antagonists, as well as activators or inhibitors of PPAR alpha, which controls the expression of genes involved in FAO. They also include studies in Mas1-/- Ppara-/- mice. The transcriptomic and proteomic analysis also shows that FOXO and PI3K-Akt signaling pathways are dysregulated when Mas1-deficient mice are exposed to APAP overdose. In vivo and in vitro analysis using activators and inhibitors of these signaling pathways demonstrate that Mas modulates lipophagy and FAO in hepatocytes via AKT and FOXO1-dependent pathways (Fig. 1). Following this valuable work, including the discovery of a new mechanism linking Mas activation and the beneficial effects of enhancing autophagy and FAO in APAP-induced liver injury, the fact that the Mas activator AVE0991 promoted beneficial effects 2 hours post-APAP overdose but not when given 24 to 48 hours post-APAP, shows that more knowledge is required to prolong the benefits of enhancing lipophagy and FAO. The results of the current work are based on the metabolic reprogramming of hepatocytes. However, in the context of liver fibrosis, Ang-(1–7) has also been shown to play important roles in other liver cell types. Ang-(1–7) mitigates the activation of hepatic stellate cells, the main fibrogenic cells in the liver, by modulating lipid metabolism, more precisely reducing malonyl coenzyme A decarboxylase and thereby inhibiting fatty acid synthesis.[17]de Oliveira da Silva B. Alberici L.C. Ramos L.F. Silva C.M. da Silveira M.B. Dechant C.R.P. et al.Altered global microRNA expression in hepatic stellate cells LX-2 by angiotensin-(1-7) and miRNA-1914-5p identification as regulator of pro-fibrogenic elements and lipid metabolism.Int J Biochem Cel Biol. 2018; 98: 137-155Crossref PubMed Scopus (12) Google Scholar In addition, Ang-(1–7) increases the number of Kupffer cells in the liver.[18]Wen S.W. Ager E.I. Neo J. Christophi C. The renin angiotensin system regulates Kupffer cells in colorectal liver metastases.Cancer Biol Ther. 2013; 14: 720-727Crossref PubMed Scopus (24) Google Scholar Therefore, it may be of interest to address whether targeting other cell types could increase and/or prolong the protective effect of Mas against APAP-induced liver injury. Another key question is whether the benefits of activating the Ang-(1–7)/Mas axis to treat different liver diseases could be translated into the design of a drug with potential to reach patients. The clinical relevance of the RAS is beyond doubt, since Ang converting enzyme inhibitors and Ang II receptor antagonists have become one of the most successful therapeutic strategies in patients with hypertension and hypertension-associated pathological disorders. The RAS antagonists also attenuate fibrosis progression in both animal and human studies.[19]Abbas G. Silveira M.G. Lindor K.D. Hepatic fibrosis and the renin-angiotensin system.Am J Ther. 2011; 18: e202-e208Crossref PubMed Scopus (28) Google Scholar Considering that the Ang-(1–7)/Mas axis acts as a counter-regulatory system against the Ang II receptor pathway, agonists of Ang-(1–7) are desirable. The first discovered Ang-(1–7) analog was AVE0991,[20]Wiemer G. Dobrucki L.W. Louka F.R. Malinski T. Heitsch H. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium.Hypertension. 2002; 40: 847-852Crossref PubMed Scopus (154) Google Scholar which was shown to exert protective effects against APAP-induced liver injury.[16]Chen S. Lu Z. Jia H. Yang B. Liu C. Yang Y. et al.Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice.J Hepatol. 2023; 78: 543-557Abstract Full Text Full Text PDF Scopus (1) Google Scholar This compound is a non-peptide and an orally active Mas agonist that mimics the effects of Ang-(1–7) in several organs and tissues, such as vessels, kidney, and heart. Despite showing promising preclinical actions, decreasing blood pressure and exerting renoprotective effects, it has never been tested in clinical studies. However, other Ang-(1–7) analogs and different preparations have been developed and some of them have been approved for distinct purposes. For instance, TXA127 is being used in patients with Duchenne muscular dystrophy or congenital muscular dystrophy[21]Wester A. Devocelle M. Tallant E.A. Chappell M.C. Gallagher P.E. Paradisi F. Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.Amino Acids. 2017; 49: 1733-1742Crossref PubMed Scopus (14) Google Scholar and the safety and efficacy of topical DSC127 in accelerating the healing of diabetic foot ulcers has been assessed in phase III trials.[22]Rodgers K.E. Bolton L.L. Verco S. diZerega G.S. NorLeu(3)-Angiotensin (1-7) [DSC127] as a therapy for the healing of diabetic foot ulcers.Adv Wound Care (New Rochelle). 2015; 4: 339-345Crossref PubMed Google Scholar The study by Chen S, Lu Z, Jia H, Yang B et al.[16]Chen S. Lu Z. Jia H. Yang B. Liu C. Yang Y. et al.Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice.J Hepatol. 2023; 78: 543-557Abstract Full Text Full Text PDF Scopus (1) Google Scholar reveals Mas agonists’ therapeutic potential in APAP-induced liver injury, but there is still a long journey ahead, since the clinical efficacy and safety of these agonists (Mas is ubiquitously expressed, increasing the risk of undesirable side effects) in patients with drug-induced liver injury remain to be established. This work was supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT1476-22) and MCIU/AEI/FEDER, UE (PID2021-124425OB-I00 to P.A. and PID2021-126096NB-I00 and RED2018-102379-T to R.N.); Xunta de Galicia (2021-CP085 and 2020-PG0157); the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331). The Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and the Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. RN and PA organized, wrote the manuscript and prepared the figure. The following are the supplementary data to this article: Download .pdf (.31 MB) Help with pdf files Multimedia component 1" @default.
• W4313367777 created "2023-01-06" @default.
• W4313367777 creator A5020982137 @default.
• W4313367777 creator A5072954162 @default.
• W4313367777 date "2023-03-01" @default.
• W4313367777 modified "2023-10-16" @default.
• W4313367777 title "Expanding the roles of the renin–angiotensin system: Drug-induced liver injury" @default.
• W4313367777 cites W1966174134 @default.
• W4313367777 cites W1995966034 @default.
• W4313367777 cites W2003942160 @default.
• W4313367777 cites W2004325124 @default.
• W4313367777 cites W2004840558 @default.
• W4313367777 cites W2007505836 @default.
• W4313367777 cites W2018166539 @default.
• W4313367777 cites W2024952451 @default.
• W4313367777 cites W2026437193 @default.
• W4313367777 cites W2047667443 @default.
• W4313367777 cites W2066987174 @default.
• W4313367777 cites W2073820873 @default.
• W4313367777 cites W2147194311 @default.
• W4313367777 cites W2159872857 @default.
• W4313367777 cites W2164685899 @default.
• W4313367777 cites W2207463207 @default.
• W4313367777 cites W2737518257 @default.
• W4313367777 cites W2738050484 @default.
• W4313367777 cites W2789378095 @default.
• W4313367777 cites W2914225706 @default.
• W4313367777 cites W3093059081 @default.
• W4313367777 cites W4308740088 @default.
• W4313367777 doi "https://doi.org/10.1016/j.jhep.2022.12.016" @default.
• W4313367777 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36592643" @default.
• W4313367777 hasPublicationYear "2023" @default.
• W4313367777 type Work @default.
• W4313367777 citedByCount "0" @default.
• W4313367777 crossrefType "journal-article" @default.
• W4313367777 hasAuthorship W4313367777A5020982137 @default.
• W4313367777 hasAuthorship W4313367777A5072954162 @default.
• W4313367777 hasBestOaLocation W43133677771 @default.
• W4313367777 hasConcept C126322002 @default.
• W4313367777 hasConcept C170493617 @default.
• W4313367777 hasConcept C198710026 @default.
• W4313367777 hasConcept C2776637226 @default.
• W4313367777 hasConcept C2780035454 @default.
• W4313367777 hasConcept C2908929049 @default.
• W4313367777 hasConcept C71924100 @default.
• W4313367777 hasConcept C84393581 @default.
• W4313367777 hasConcept C98274493 @default.
• W4313367777 hasConceptScore W4313367777C126322002 @default.
• W4313367777 hasConceptScore W4313367777C170493617 @default.
• W4313367777 hasConceptScore W4313367777C198710026 @default.
• W4313367777 hasConceptScore W4313367777C2776637226 @default.
• W4313367777 hasConceptScore W4313367777C2780035454 @default.
• W4313367777 hasConceptScore W4313367777C2908929049 @default.
• W4313367777 hasConceptScore W4313367777C71924100 @default.
• W4313367777 hasConceptScore W4313367777C84393581 @default.
• W4313367777 hasConceptScore W4313367777C98274493 @default.
• W4313367777 hasIssue "3" @default.
• W4313367777 hasLocation W43133677771 @default.
• W4313367777 hasLocation W43133677772 @default.
• W4313367777 hasOpenAccess W4313367777 @default.
• W4313367777 hasPrimaryLocation W43133677771 @default.
• W4313367777 hasRelatedWork W1989591433 @default.
• W4313367777 hasRelatedWork W2008559461 @default.
• W4313367777 hasRelatedWork W2033713032 @default.
• W4313367777 hasRelatedWork W2042660006 @default.
• W4313367777 hasRelatedWork W2126797993 @default.
• W4313367777 hasRelatedWork W2149410839 @default.
• W4313367777 hasRelatedWork W2151139437 @default.
• W4313367777 hasRelatedWork W2151226843 @default.
• W4313367777 hasRelatedWork W2190649397 @default.
• W4313367777 hasRelatedWork W2744890335 @default.
• W4313367777 hasVolume "78" @default.
• W4313367777 isParatext "false" @default.
• W4313367777 isRetracted "false" @default.
• W4313367777 workType "article" @default.