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Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.
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OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.
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Ayuno , Lisosomas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Humanos , Lisosomas/metabolismo , Ayuno/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Ratones Endogámicos C57BL , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Masculino , Hepatocitos/metabolismo , Biosíntesis de Proteínas , Autofagia , Hígado/metabolismo , Ratones NoqueadosRESUMEN
Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action have been associated with genetic and endocrine diseases in man. Over the past few years, there has been renewed interest in TH action and the therapeutic potential of THs and thyromimetics to treat several metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. Recent advances in the development of tissue and TH receptor isoform-targeted thyromimetics have kindled new hope for translating our fundamental understanding of TH action into an effective therapy. This review provides a concise overview of the historical development of our understanding of TH action, its physiological and pathophysiological effects on metabolism, and future therapeutic applications to treat metabolic dysfunction.
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Hormonas Tiroideas , Humanos , Hormonas Tiroideas/metabolismo , Animales , Enfermedades Metabólicas/metabolismo , Receptores de Hormona Tiroidea/metabolismoRESUMEN
Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.
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LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.
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Non-alcoholic steatohepatitis (NASH) is a condition characterized by inflammation and hepatic injury/fibrosis caused by the accumulation of ectopic fats in the liver. Recent advances in lipidomics have allowed the identification and characterization of lipid species and have revealed signature patterns of various diseases. Here, we describe a lipidomics workflow to assess the lipid profiles of liver homogenates taken from a NASH mouse model. The protocol described below was used to extract and analyze the metabolites from the livers of mice with NASH by liquid chromatography-mass spectrometry (LC-MS); however, it can be applied to other tissue homogenate samples. Using this method, over 1,000 species of lipids from five classes can be analyzed in a single run on the LC-MS. Also, partial elucidation of the identity of neutral lipid (triacylglycerides and diacylglycerides) aliphatic chains can be performed with this simple LC-MS setup. Key features Over 1,000 lipid species (sphingolipids, cholesteryl esters, neutral lipids, phospholipids, fatty acids) are analyzed in one run. Analysis of liver lipids in non-alcoholic steatohepatitis (NASH) mouse model. Normal-phase chromatography coupled to a triple quadrupole mass spectrometer.
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Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using Clustered Regularly Interspaced Short Palindromic Repeats/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic ratio of reduced versus oxidized form of nicotinamide adenine dinucleotide (NAD) and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.
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Citrulinemia , Hiperamonemia , Humanos , Citrulinemia/genética , Citrulinemia/metabolismo , NAD/metabolismo , Malatos , Ácido Aspártico/metabolismo , Hiperamonemia/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Hepatocitos/metabolismo , Glucólisis , Urea/metabolismo , Ácidos GrasosRESUMEN
Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Carcinoma Hepatocelular/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid ß-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.
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Enfermedad del Hígado Graso no Alcohólico , Espermidina , Animales , Ácidos Grasos , Lisina/metabolismo , Ratones , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Factores de Iniciación de Péptidos/genética , Factores de Iniciación de Péptidos/metabolismo , Espermidina/farmacologíaRESUMEN
BACKGROUND & AIMS: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH. METHODS: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture. RESULTS: Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated ß -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. CONCLUSIONS: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH. LAY SUMMARY: The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis.
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Hiperhomocisteinemia , Enfermedad del Hígado Graso no Alcohólico , Animales , Ácidos Grasos , Fibrosis , Ácido Fólico , Homocisteína , Humanos , Inflamación , Metionina , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Proteínas Qa-SNARE , Vitamina B 12 , VitaminasRESUMEN
Background: Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, lobular inflammation, and fibrosis. Thyroid hormone (TH) reduces steatosis; however, the therapeutic effect of TH on NASH-associated inflammation and fibrosis is not known. This study examined the therapeutic effect of TH on hepatic inflammation and fibrosis during NASH and investigated THs molecular actions on autophagy and mitochondrial biogenesis. Methods: HepG2-TRß cells were treated with bovine serum albumin-conjugated palmitic acid (PA) to mimic lipotoxic conditions in vitro. Mice with NASH were established by feeding C57BL/6J mice Western diet with 15% fructose in drinking water for 16 weeks. These mice were administered triiodothyronine (T3)/thyroxine (T4) supplemented in drinking water for the next eight weeks. Results: In cultured HepG2-TRß cells, TH treatment increased mitochondrial respiration and fatty acid oxidation under basal and PA-treated conditions, as well as decreased lipopolysaccharides and PA-stimulated inflammatory and fibrotic responses. In a dietary mouse model of NASH, TH administration decreased hepatic triglyceride content (3.19 ± 0.68 vs. 8.04 ± 0.42 mM/g liver) and hydroxyproline (1.44 ± 0.07 vs. 2.58 ± 0.30 mg/g liver) when compared with mice with untreated NASH. Metabolomics profiling of lipid metabolites showed that mice with NASH had increased triacylglycerol, diacylglycerol, monoacylglycerol, and hepatic cholesterol esters species, and these lipid species were decreased by TH treatment. Mice with NASH also showed decreased autophagic degradation as evidenced by decreased transcription Factor EB and lysosomal protease expression, and accumulation of LC3B-II and p62. TH treatment restored the level of lysosomal proteins and resolved the accumulation of LC3B-II and p62. Impaired mitochondrial biogenesis was also restored by TH. The simultaneous restoration of autophagy and mitochondrial biogenesis by TH increased ß-oxidation of fatty acids. Additionally, the elevated oxidative stress and inflammasome activation in NASH liver were also decreased by TH. Conclusions: In a mouse model of NASH, TH restored autophagy and mitochondrial biogenesis to increase ß-oxidation of fatty acids and to reduce lipotoxicity, oxidative stress, hepatic inflammation, and fibrosis. Activating thyroid hormone receptor in the liver may represent an effective strategy for NASH treatment.
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Agua Potable , Enfermedad del Hígado Graso no Alcohólico , Animales , Modelos Animales de Enfermedad , Agua Potable/metabolismo , Ácidos Grasos/metabolismo , Fibrosis , Humanos , Inflamación/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hormonas Tiroideas/metabolismo , Triglicéridos/metabolismoRESUMEN
Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an in vivo vascular injury model of restenosis. Furthermore, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of MTOR signaling in these cells. Genetic deletion of the key autophagy gene Atg5, and the Sqstm1/p62 gene encoding a receptor protein, showed that the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased WNT-signaling and the expression of two WNT target genes, Axin2 and Ccnd1 (cyclin D1). This effect was mediated by autophagic degradation of a key member of the WNT signaling cascade, DVL2, by caffeine to decrease WNT signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and DVL2 were also shown to interact with each other, and the overexpression of DVL2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings demonstrated that caffeine reduced VSMC proliferation by inhibiting WNT signaling via stimulation of autophagy, thus reducing the vascular restenosis. Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.
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Autofagia , Músculo Liso Vascular , Animales , Autofagia/fisiología , Cafeína/metabolismo , Cafeína/farmacología , Proliferación Celular , Células Cultivadas , Humanos , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína Sequestosoma-1/metabolismo , Vía de Señalización WntRESUMEN
PURPOSE: Noise in the operating room (OR) is common and associated with negative effects on anesthesiologists, surgeons, and patient outcomes. Induction of anesthesia is among the loudest perioperative periods. Despite its critical nature, there is little data on noise levels during induction, associated patient and anesthesiologist satisfaction, and the effects of noise reduction strategies. METHODS: We conducted a two-part prospective interventional quality improvement project on the care of adult patients receiving general anesthesia for elective noncardiac surgery. For part A, we measured average and peak noise (dB[A]) levels during anesthesia induction in N = 100 cases and administered a satisfaction questionnaire to anesthesiologists. We then applied a multidisciplinary educational program to OR personnel on active noise reduction strategies and subsequently collected data during N = 109 cases in a post-intervention phase. For part B, we administered satisfaction questionnaires to N = 100 patients pre- vs postintervention, respectively. RESULTS: Median [interquartile range] noise levels throughout induction were 66.0 [62.5-68.6] dB(A) preintervention vs 63.5 [60.1-65.4] dB[A] post-intervention (Hodges-Lehmann estimator of the difference, - 2.7 dB[A]; 95% confidence interval [CI], - 4.0 to - 1.5; P < 0.001). Peak noise levels during induction were 87.3 [84.0-90.5] dB(A) preintervention and 86.2 [81.8-89.3] dB(A) postintervention (Hodges-Lehmann estimator of the difference, - 1.8 dB[A]; 95% CI, - 3.3 to - 0.3; P = 0.02). Noise-related anesthesiologist satisfaction postintervention was significantly improved in multiple domains, including assessment of noise having distracted anesthesiologists. Patient satisfaction was high pre-intervention and did not significantly improve further. CONCLUSION: In this quality improvement project, average noise levels during induction of anesthesia, anesthesiologist satisfaction, and anesthesiologists' perceived ability to perform were improved following a multidisciplinary educational program on noise reduction in the OR. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04204785); registered 19 December 2019.
RéSUMé: OBJECTIF: Le bruit en salle d'opération (SOP) est fréquent et associé à des effets négatifs sur les anesthésiologistes, les chirurgiens et les issues des patients. L'induction de l'anesthésie est l'une des périodes périopératoires les plus bruyantes. Malgré sa nature critique, il existe peu de données sur les niveaux sonores pendant l'induction, la satisfaction des patients et des anesthésiologistes qui y est reliée, et les effets des stratégies de réduction du bruit. MéTHODE: Nous avons mené un projet prospectif et interventionnel, en deux parties, d'amélioration de la qualité sur les soins aux patients adultes recevant une anesthésie générale pour une chirurgie non cardiaque non urgente. Dans le cadre de la première partie A, nous avons mesuré les niveaux de bruit moyen et maximaux (dB[A]) pendant l'induction de l'anesthésie dans n = 100 cas et administré un questionnaire de satisfaction aux anesthésiologistes. Nous avons ensuite appliqué un programme de formation multidisciplinaire au personnel de la salle d'opération sur les stratégies de réduction active du bruit et avons ensuite recueilli des données pour n = 109 cas dans une phase post-intervention. Pour la deuxième partie B, nous avons administré des questionnaires de satisfaction à n = 100 patients pré- vs post-intervention, respectivement. RéSULTATS: Les niveaux de bruit médians [écart interquartile] tout au long de l'induction étaient de 66,0 [62,568,6] dB(A) avant l'intervention vs 63,5 [60,165,4] dB[A] après l'intervention (estimateur de Hodges-Lehmann, − 2,7 dB[A]; intervalle de confiance [IC] 95 %, − 4,0 à − 1,5; P < 0,001). Les niveaux maximaux de bruit pendant l'induction étaient de 87,3 [84,090,5] dB(A) avant l'intervention et de 86,2 [81,889,3] dB(A) après l'intervention (estimateur de Hodges-Lehmann, − 1,8 dB[A]; IC 95 %, − 3,3 à − 0,3; P = 0,02). La satisfaction des anesthésiologistes par rapport au bruit après l'intervention a été considérablement améliorée dans de nombreux domaines, y compris l'évaluation du bruit ayant distrait les anesthésiologistes. La satisfaction des patients était élevée avant l'intervention et ne s'est pas améliorée de manière significative. CONCLUSION: Dans ce projet d'amélioration de la qualité, les niveaux de bruit moyens lors de l'induction de l'anesthésie, la satisfaction des anesthésiologistes et la capacité perçue des anesthésiologistes à réaliser leurs tâches ont été améliorés à la suite d'un programme de formation multidisciplinaire sur la réduction du bruit en salle d'opération. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04204785); enregistrée le 19 décembre 2019.
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Anestesiología , Quirófanos , Adulto , Anestesia General , Humanos , Estudios Prospectivos , Mejoramiento de la CalidadRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. It comprises simple steatosis and non-alcoholic steatohepatitis (NASH), which can further progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD involves genetic, environmental, and endocrine factors, and several molecular mechanisms have been identified. In this review, we discuss the recent findings on the role of autophagy, in particular lipophagy and mitophagy, in hepatic lipid oxidation. We discuss the pre-clinical and clinical evidence suggesting that impairment of autophagy exacerbates NAFLD progression and restoration of autophagy exerts beneficial effects on NAFLD. We discuss how thyroid hormone (TH) simultaneously regulates lipophagy, mitophagy, and mitochondrial biogenesis to increase ß-oxidation of fatty acids and reduce steatosis in the liver. Lastly, we discuss the recent clinical progress in using TH or thyromimetics in treating NAFLD/NASH.
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Hormone synthesis and secretion is a highly regulated process governed by metabolic cues. Although peptide hormone action is largely governed by the rate of its synthesis and secretion by endocrine cells, and the levels of its receptors on the target cells, intracellular degradation of the hormone-containing secretory vesicles by lysosomes (crinophagy) adds an additional layer of regulation. In our recent study, we uncovered the regulatory mechanism governing the crinophagic turnover of GCG (glucagon), a glycoprotein hormone secreted by pancreatic α-cells. Our results showed that inhibition of MTORC1 induces crinophagy-mediated degradation of glucagon and decreases its secretion in response to hypoglycemia. Furthermore, we demonstrated that crinophagy-regulated glucagon turnover does not involve macroautophagy. These results suggest that modulation of crinophagy may serve as a novel therapeutic strategy to regulate hormone secretion in endocrine and metabolic pathologies.
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Autofagia , Glucagón , Autofagia/fisiología , Glucagón/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Vesículas Secretoras/metabolismoRESUMEN
OBJECTIVE: Crinophagy is a secretory granule-specific autophagic process that regulates hormone content and secretion in endocrine cells. However, despite being one of the earliest described autophagic processes, its mechanism of action and regulation in mammalian cells remains unclear. METHODS AND RESULTS: Here, we examined mammalian crinophagy and its modulation that regulate hormone secretion in a glucagon-producing mouse pancreatic α-cell line, alpha TC1 clone 9 (αTC9), and in vivo. Western blot, electron microscopy, and immunofluorescence analyses were performed to study crinophagy and glucagon secretion in αTC9 cells and C57BL/6 mice, in response to the mammalian target of rapamycin complex 1 (MTORC1) inhibitor rapamycin. Amino acid depletion and pharmacological inhibition of MTORC1 increased the shuttling of glucagon-containing secretory granules into lysosomes for crinophagic degradation to reduce glucagon secretion through a macroautophagy-independent mechanism. Furthermore, MTORC1 inhibition reduced both intracellular and secreted glucagon in rapamycin-treated mice, in response to hypoglycaemia. CONCLUSION: In summary, we have identified a novel crinophagic mechanism of intracellular glucagon turnover in pancreatic α-cells regulated by MTORC1 signalling.