SIMPLE Is an Endosomal Regulator That Protects Against NAFLD by Targeting the Lysosomal Degradation of EGFR.
Animals
Biopsy
Cells, Cultured
DNA-Binding Proteins
/ antagonists & inhibitors
Diet, High-Fat
/ adverse effects
ErbB Receptors
/ antagonists & inhibitors
Female
Gene Knockdown Techniques
Hepatocytes
Humans
Lipid Metabolism
/ drug effects
Liver
/ metabolism
Lysosomes
/ metabolism
Male
Mice
Mice, Knockout
Non-alcoholic Fatty Liver Disease
/ etiology
Nuclear Proteins
/ genetics
Primary Cell Culture
Proteolysis
Transcription Factors
/ antagonists & inhibitors
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
25
06
2021
received:
12
05
2021
accepted:
28
06
2021
pubmed:
29
7
2021
medline:
15
1
2022
entrez:
28
7
2021
Statut:
ppublish
Résumé
NAFLD has become a tremendous burden for public health; however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus, and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling, but the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein. This study found that in vitro knockdown of SIMPLE significantly aggravated lipid accumulation and inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-induced, high-fat-high-cholesterol diet (HFHC)-induced, and methionine-choline-deficient diet (MCD)-induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal chow (NC) diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation, and fibrosis in Simple-HKO mice compared with control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, thus exaggerating NAFLD development. Moreover, we demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE. SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.
Sections du résumé
BACKGROUND AND AIMS
NAFLD has become a tremendous burden for public health; however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus, and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling, but the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein.
APPROACH AND RESULTS
This study found that in vitro knockdown of SIMPLE significantly aggravated lipid accumulation and inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-induced, high-fat-high-cholesterol diet (HFHC)-induced, and methionine-choline-deficient diet (MCD)-induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal chow (NC) diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation, and fibrosis in Simple-HKO mice compared with control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, thus exaggerating NAFLD development. Moreover, we demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE.
CONCLUSIONS
SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.
Substances chimiques
DNA-Binding Proteins
0
LITAF protein, human
0
Litaf protein, mouse
0
Nuclear Proteins
0
Transcription Factors
0
EGFR protein, human
EC 2.7.10.1
EGFR protein, mouse
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3091-3109Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
Références
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686-690.
Yu Y, Cai J, She Z, Li H. Insights into the epidemiology, pathogenesis, and therapeutics of nonalcoholic fatty liver diseases. Adv Sci (Weinh) 2019;6:1801585.
Sivell C. Nonalcoholic fatty liver disease: a silent epidemic. Gastroenterol Nurs 2019;42:428-434.
Cai J, Zhang X-J, Ji Y-X, Zhang P, She Z-G, Li H. Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases. Circ Res 2020;126:679-704.
Chen Z, Yu Y, Cai J, Li H. Emerging molecular targets for treatment of nonalcoholic fatty liver disease. Trends Endocrinol Metab 2019;30:903-914.
Hipolito VEB, Diaz JA, Tandoc KV, Oertlin C, Ristau J, Chauhan N, et al. Enhanced translation expands the endo-lysosome size and promotes antigen presentation during phagocyte activation. PLoS Biol 2019;17:e3000535.
Du J, Ji Y, Qiao L, Liu Y, Lin J. Cellular endo-lysosomal dysfunction in the pathogenesis of non-alcoholic fatty liver disease. Liver Int 2020;40:271-280.
Scita G, Di Fiore PP. The endocytic matrix. Nature 2010;463:464-473.
Maxfield FR. Role of endosomes and lysosomes in human disease. Cold Spring Harb Perspect Biol 2014;6:a016931.
Vos DY, van de Sluis B. Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD). Mol Metab 2021;101146.
Lizunov VA, Lee J-P, Skarulis MC, Zimmerberg J, Cushman SW, Stenkula KG. Impaired tethering and fusion of GLUT4 vesicles in insulin-resistant human adipose cells. Diabetes 2013;62:3114-3119.
Fedoseienko A, Wijers M, Wolters JC, Dekker D, Smit M, Huijkman N, et al. The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking. Circ Res 2018;122:1648-1660.
Maianu L, Keller SR, Garvey WT. Adipocytes exhibit abnormal subcellular distribution and translocation of vesicles containing glucose transporter 4 and insulin-regulated aminopeptidase in type 2 diabetes mellitus: implications regarding defects in vesicle trafficking. J Clin Endocrinol Metab 2001;86:5450-5456.
Barbieri M, Esposito A, Angellotti E, Rizzo MR, Marfella R, Paolisso G. Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease. PLoS One 2013;8:e71391.
Zeigerer A, Bogorad R, Sharma K, Gilleron J, Seifert S, Sales S, et al. Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep 2015;11:884-892.
Vassilopoulos S, Esk C, Hoshino S, Funke BH, Chen C-Y, Plocik AM, et al. A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism. Science 2009;324:1192-1196.
Zhao GN, Zhang P, Gong J, Zhang XJ, Wang PX, Yin M, et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 2017;23:742-752.
Moriwaki Y, Begum NA, Kobayashi M, Matsumoto M, Toyoshima K, Seya T. Mycobacterium bovis bacillus calmette-guerin and its cell wall complex induce a novel lysosomal membrane protein, SIMPLE, that bridges the missing link between lipopolysaccharide and p53-inducible gene, LITAF(PIG7), and estrogen-inducible gene, EET-1. J Biol Chem 2001;276:23065-23076.
Shirk AJ, Anderson SK, Hashemi SH, Chance PF, Bennett CL. SIMPLE interacts with NEDD4 and TSG101: evidence for a role in lysosomal sorting and implications for Charcot-Marie-Tooth disease. J Neurosci Res 2005;82:43-50.
Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, Hausmanowa-Petrusewicz I, et al. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat 2005;25:372-383.
Lee SM, Chin L-S, Li L. Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. J Cell Biol 2012;199:799-816.
Chin L-S, Lee SM, Li L. SIMPLE: A new regulator of endosomal trafficking and signaling in health and disease. Commun Integr Biol 2013;6:e24214.
Somandin C, Gerber D, Pereira JA, Horn M, Suter U. LITAF (SIMPLE) regulates Wallerian degeneration after injury but is not essential for peripheral nerve development and maintenance: implications for Charcot-Marie-Tooth disease. Glia 2012;60:1518-1528.
Lee SM, Olzmann JA, Chin L-S, Li L. Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J Cell Sci 2011;124(Pt 19):3319-3331.
Liu Y, Song J, Yang J, Zheng J, Yang L, Gao J, et al. Tumor necrosis factor-α-induced protein 8-like 2 alleviates nonalcoholic fatty liver disease via suppressing TAK1 activation. Hepatology 2021;74:1300-1318.
Zhang P, Wang P-X, Zhao L-P, Zhang X, Ji Y-X, Zhang X-J, et al. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med 2018;24:84-94.
Bhushan B, Banerjee S, Paranjpe S, Koral K, Mars WM, Stoops JW, et al. Pharmacologic inhibition of epidermal growth factor receptor suppresses nonalcoholic fatty liver disease in a murine fast-food diet model. Hepatology 2019;70:1546-1563.
Zhou J, Zhou F, Wang W, Zhang XJ, Ji YX, Zhang P, et al. Epidemiological features of NAFLD from 1999 to 2018 in China. Hepatology 2020;71:1851-1864.
Tang X, Fenton MJ, Amar S. Identification and functional characterization of a novel binding site on TNF-alpha promoter. Proc Natl Acad Sci U S A 2003;100(7):4096-4101. https://doi.org/10.1073/pnas.0630562100
Eaton HE, Metcalf J, Lacerda AF, Brunetti CR. Accumulation of endogenous LITAF in aggresomes. PLoS One 2012;7:e30003.
Lacerda AF, Hartjes E, Brunetti CR. LITAF mutations associated with charcot-marie-tooth disease 1C show mislocalization from the late endosome/lysosome to the mitochondria. PLoS One 2014;9(7):e103454. https://doi.org/10.1371/journal.pone.0103454
Huang Y, Bennett CL. Litaf/Simple protein is increased in intestinal tissues from patients with CD and UC, but is unlikely to function as a transcription factor. Inflamm Bowel Dis 2007;13:120-121.
Ho AK, Wagstaff JL, Manna PT, Wartosch L, Qamar S, Garman EF, et al. The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C. BMC Biol 2016;14:109.
Moshal KS, Roder K, Kabakov AY, Werdich AA, Chiang D-E, Turan NN, et al. LITAF (lipopolysaccharide-induced tumor necrosis factor) regulates cardiac L-type calcium channels by modulating NEDD (neural precursor cell expressed developmentally downregulated protein) 4-1 ubiquitin ligase. Circ Genom Precis Med 2019;12:407-420.
Ceccarelli S, Panera N, Mina M, Gnani D, De Stefanis C, Crudele A, et al. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. Oncotarget 2015;6:41434-41452.
Zhu H, Guariglia S, Yu RYL, Li W, Brancho D, Peinado H, et al. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Biol Cell 2013;24(11):1619-1637.
Merrill JC, You J, Constable C, Leeman SE, Amar S. Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis. Proc Natl Acad Sci U S A 2011;108:21247-21252.
Eden ER, White IJ, Futter CE. Down-regulation of epidermal growth factor receptor signaling within multivesicular bodies. Biochem Soc Trans 2009;37(Pt 1):173-177.
Burke P, Schooler K, Wiley HS. Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell 2001;12:1897-1910.
Tomas A, Futter CE, Eden ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol 2014;24:26-34.
Avraham R, Yarden Y. Feedback regulation of EGFR signaling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 2011;12(2):104-117. https://doi.org/10.1038/nrm3048
Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signaling. Nat Rev Cancer 2021;21:181-197.
Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR -mutated non-small cell lung cancer. Sci Immunol 2020;5:eaav3937.
Liang D, Chen H, Zhao L, Zhang W, Hu J, Liu Z, et al. Inhibition of EGFR attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease. Biochim Biophys Acta Mol Basis Dis 2018;1864:133-142.
Bhushan B, Michalopoulos GK. Role of epidermal growth factor receptor in liver injury and lipid metabolism: esmerging new roles for an old receptor. Chem Biol Interact 2020;324:109090.
Choung S, Kim JM, Joung KH, Lee ES, Kim HJ, Ku BJ. Epidermal growth factor receptor inhibition attenuates non-alcoholic fatty liver disease in diet-induced obese mice. PLoS One 2019;14:e0210828.
Scheving LA, Zhang X, Garcia OA, Wang RF, Stevenson MC, Threadgill DW, et al. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice. Am J Physiol Gastrointest Liver Physiol 2014;306:G370-G381.
Hampton T. New insight on preventing EGFR inhibitor-induced adverse effects. JAMA 2020;323:814.