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Hepatic Lysosomal Enzyme Activity in Primary Biliary Cholangitis

Fibrosis. 2023, 1(1), 10005; https://doi.org/10.35534/fibrosis.2023.10005
Ioannis Tsomidis 1,2    Georgios Notas 3    Argyro Voumvouraki 1    Dimitrios Samonakis 4    Mairi Koulentaki 4    Elias Kouroumalis 2,4 *   
1
1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
2
Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece
3
Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, 71500 Heraklion, Greece
4
Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Greece
*
Authors to whom correspondence should be addressed.

Received: 07 Jul 2023    Accepted: 14 Sep 2023    Published: 16 Sep 2023   

(This article belongs to the Topic Collection Hepatic Fibrosis)
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Abstract

Background: Lysosomal enzymes are implicated in autophagy and senescence. Hepatic lysosomal enzymes have not been studied in Primary Biliary Cholangitis (PBC). We therefore quantified the activities of lysosomal hydrolases in liver tissue of PBC patients. Methods: We compared enzyme activities in liver tissue from PBC patients with normal livers. Alcoholic liver disease and chronic viral disease served as disease controls. Results: Cathepsin B1 was significantly increased in early PBC (225.1 ± 18.06 mean ± SD, p < 0.0001) and reduced in later stages (66.5 ± 9.7, p = 0.004, controls 130.4 ± 14.9). It was reduced in patients with extensive fibrosis such as alcoholic and viral cirrhosis (p < 0.01 and p = 0.004 respectively) but not in chronic hepatitis. Cathepsin D was increased in early PBC (39 × 103 ± 4.8 SD, p < 0.0001) and less so in later stages (20.1 × 103 ± 3.9, p = 0.05, controls 14.1 × 103 ± 2.9). It was also increased in the presence of histological necro-inflammation in hepatitis. Treatment with ursodeoxycholate (UDCA) restored the abnormal values of enzymes in PBC. Lipid hydrolases mostly paralleled the changes of Cathepsins. Sequential measurements in serum of patients with acute alcoholic hepatitis showed that cathepsin B1 gradually decreases, and esterases increase as aminotransferases improve. Conclusions: The increased activity of lysosomal enzymes in early PBC are possibly on line with increased senescence. Treatment with UDCA restores abnormal values. In chronic liver disease, Cathepsin B1 reduction is associated with fibrosis and increased cathepsin D with necro-inflammation. Abnormalities of lysosomal enzymes indicate impairment of the final stage of autophagy in chronic liver disease.

Keywords

Acid lipase; Cathepsin; Chronic liver disease; Esterase; Lysosomal enzyme

References

1.
Lleo A, Leung PSC, Hirschfield GM, Gershwin EM. The pathogenesis of primary biliary cholangitis: a comprehensive review.  Semin. Liver Dis. 2020, 40, 34–48. [Google Scholar]
2.
Prieto J, Banales JM, Medina JF. Primary biliary cholangitis: pathogenic mechanisms.  Curr. Opin. Gastroenterol. 2021, 37, 91–98. [Google Scholar]
3.
Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases.  Gut 2021, 70, 1989–2003. [Google Scholar]
4.
Trivella J, John BV, Levy C. Primary biliary cholangitis: Epidemiology, prognosis, and treatment.  Hepatol. Commun. 2023, 7, e0179. [Google Scholar]
5.
Koulentaki M, Mantaka A, Sifaki-Pistolla D, Thalassinos E, Tzanakis N, Kouroumalis E. Geoepidemiology and space-time analysis of Primary biliary cirrhosis in Crete, Greece.  Liver Int. 2014, 34, e200–e207. [Google Scholar]
6.
Turk B, Turk D, Turk V. Lysosomal cysteine proteases: more than scavengers.  Biochim. Biophys. Acta 2000, 1477, 98–111. [Google Scholar]
7.
Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, et al. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics.  Biomedicines 2022, 10, 1288. [Google Scholar]
8.
Sasaki M, Sato Y, Nakanuma Y. An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis.  Lab. Invest. 2018, 98, 745–754. [Google Scholar]
9.
Trivedi PC, Bartlett JJ, Pulinilkunnil T. Lysosomal Biology and Function: Modern View of Cellular Debris Bin.  Cells 2020, 9, 1131. [Google Scholar]
10.
Willstätter R, Bamann E. Über die Proteasen der Magenschleimhaut. Erste Abhandlung Über die Enzyme der Leukocyten.  Hoppe-Seyler’s Zeitschrift Fur Physiologische Chemie 1929, 180, 127–143. [Google Scholar]
11.
Karch J, Schips TG, Maliken BD, Brody MJ, Sargent MA, Kanisicak O, et al. Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak.  Elife 2017, 6, e30543. [Google Scholar]
12.
Wang Y, Wu Q, Anand BG, Karthivashan G, Phukan G, Yang J, et al. Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β-amyloid-toxicity.  Neuropathol. Appl. Neurobiol. 2020, 46, 686–706. [Google Scholar]
13.
Hausmann M, Obermeier F, Schreiter K, Spottl T, Falk W, Schölmerich J, et al.  Cathepsin D is up-regulated in inflammatory bowel disease macrophages.  Clin. Exp. Immunol. 2004, 136, 157–167. [Google Scholar]
14.
Mijanovic O, Petushkova AI, Brankovic A, Turk B, Solovieva AB, Nikitkina AI, et al. Cathepsin D-Managing the Delicate Balance.  Pharmaceutics 2021, 13, 837. [Google Scholar]
15.
Iwama H, Mehanna S, Imasaka M, Hashidume S, Nishiura H, Yamamura KI, et al. Cathepsin B and D deficiency in the mouse pancreas induces impaired autophagy and chronic pancreatitis.  Sci. Rep. 2021, 11, 6596. [Google Scholar]
16.
Senjor E, Kos J, Nanut MP. Cysteine Cathepsins as therapeutic targets in immune regulation and immune disorders.  Biomedicines 2023, 11, 476. [Google Scholar]
17.
Vidak E, Javoršek U, Vizovišek M, Turk B. Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment.  Cells 2019, 8, 264. [Google Scholar]
18.
Singh R, Cuervo AM.  Lipophagy: connecting autophagy and lipid metabolism.  Int. J. Cell. Biol. 2012, 2012, 282041. [Google Scholar]
19.
Pajed L, Wagner C, Taschler U, Schreiber R, Kolleritsch S, Fawzy N, et al. Hepatocyte-specific deletion of lysosomal acid lipase leads to cholesteryl ester but not triglyceride or retinyl ester accumulation.  J. Biol. Chem. 2019, 294, 9118–9133. [Google Scholar]
20.
Uphoff CC, Drexler HG. Biology of monocyte-specific esterase.  Leuk Lymphoma 2000, 39, 257–270. [Google Scholar]
21.
Nowosad A, Besson A. Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness.  Int. J. Mol. Sci. 2022, 23, 2290. [Google Scholar]
22.
Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Autophagy may precede cellular senescence of bile ductular cells in ductular reaction in primary biliary cirrhosis.  Dig. Dis. Sci. 2012, 57, 660–666. [Google Scholar]
23.
Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis.  Liver Int. 2013, 33, 312–320. [Google Scholar]
24.
van de Graaf S, Beuers U. Autophagy—another piece of the puzzle towards understanding primary biliary cirrhosis? Liver Int. 2014, 34, 481–483. [Google Scholar]
25.
Osonoi Y, Mita T, Azuma K, Nakajima K, Masuyama A, Goto H, et al. Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis.  Autophagy. 2018, 14, 1991–2006. [Google Scholar]
26.
Pla A, Pascual M, Renau-Piqueras J, Guerri C. TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain.  Cell Death Dis. 2014, 5, e1066. [Google Scholar]
27.
Wu P, Yuan X, Li F, Zhang J, Zhu W, Wei M, et al. Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure.  Circ. Heart Fail. 2017, 10, e004044. [Google Scholar]
28.
Zeng J, Acin-Perez R, Assali EA, Martin A, Brownstein AJ, Petcherski A, et al. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.  Nat. Commun. 2023, 14, 2573. [Google Scholar]
29.
Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).  Virchows Arch. A Pathol. Anat. Histol. 1978, 379, 103–112. [Google Scholar]
30.
European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis.  J. Hepatol. 2017, 67, 145–172. [Google Scholar]
31.
Roth JS, Losty T, Wierbicki E. Assay of proteolytic enzyme activity using a 14C-labeled hemoglobin.  Anal. Biochem. 1971, 42, 214–221. [Google Scholar]
32.
Barrett AJ. A new assay for cathepsin B1 and other thiol proteinases.  Anal Biochem. 1972, 47, 280–293. [Google Scholar]
33.
Van Berkel TJ, Vaandrager H, Kruijt JK, Koster JF. Characteristics of acid lipase and acid cholesteryl esterase activity in parenchymal and non-parenchymal rat liver cells.  Biochim. Biophys. Acta 1980, 617, 446–457. [Google Scholar]
34.
Schaffner T, Elner VM, Bauer M, Wissler RW. Acid lipase: a histochemical and biochemical study using triton X100-naphtyl palmitate micelles.  J. Histochem. Cytochem. 1978, 26, 696–712. [Google Scholar]
35.
Kolios G, Valatas V, Psilopoulos D, Petraki K, Kouroumalis E. Depletion of non specific esterase activity in the colonic mucosa of patients with ulcerative colitis.  Eur. J. Clin. Invest. 2002, 32, 265–273. [Google Scholar]
36.
Kouroumalis E, Hopwood D, Ross PE, Bouchier IA. Human gallbladder epithelium: non-specific esterases in cholecystitis.  J. Pathol. 1984, 142, 151–159. [Google Scholar]
37.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent.  J. Biol. Chem 1951, 193, 265–275. [Google Scholar]
38.
Wang J, Zheng M, Yang X, Zhou X, Zhang S. The Role of Cathepsin B in Pathophysiologies of Non-tumor and Tumor tissues: A Systematic Review. J. Cancer 2023, 14, 2344–2358. [Google Scholar]
39.
Menon J, Shanmugam N, Srinivas S, Vij M, Jalan A, Srinivas Reddy M, et al. Wolman's Disease: A Rare Cause of Infantile Cholestasis and Cirrhosis.  J. Pediatr. Genet. 2020, 11, 132–134. [Google Scholar]
40.
Cortner JA, Coates PM, Swoboda E, Schnatz JD. Genetic variation of lysosomal acid lipase.  Pediatr. Res. 1976, 10, 927–932. [Google Scholar]
41.
Panzitt K, Fickert P, Wagner M. Regulation of autophagy by bile acids and in cholestasis—CholestoPHAGY or CholeSTOPagy.  Biochim. Biophys. Acta Mol. Basis Dis. 2021, 1867, 166017. [Google Scholar]
42.
Sasaki M, Ikeda H, Yamaguchi J, Nakada S, Nakanuma Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence.  Hepatology 2008, 48, 186–195. [Google Scholar]
43.
Sasaki M, Yoshimura-Miyakoshi M, Sato Y, Nakanuma Y. A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis.  J. Gastroenterol. 2015, 50, 984–995. [Google Scholar]
44.
Nakanuma Y, Sasaki M, Harada K.  Autophagy and senescence in fibrosing cholangiopathies.  J. Hepatol. 2015, 62, 934–945. [Google Scholar]
45.
Rovira M, Sereda R, Pladevall-Morera D, Ramponi V, Marin I, Maus M, et al. The lysosomal proteome of senescent cells contributes to the senescence secretome.  Aging Cell 2022, 21, e13707. [Google Scholar]
46.
Bogert PS, O’Hara SP, LaRusso NF. Cellular senescence in the cholangiopathies.  Curr. Opin. Gastroenterol. 2022, 38, 121–127. [Google Scholar]
47.
Baskin-Bey ES, Canbay A, Bronk SF, Werneburg N, Guicciardi ME, Nyberg SL, et al. Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury.  Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G396–G402. [Google Scholar]
48.
Colletti GA, Miedel MT, Quinn J, Andharia N, Weisz OA, Kiselyov K. Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis.  J. Biol. Chem. 2012, 287, 8082–8091. [Google Scholar]
49.
de Castro MA, Bunt G, Wouters FS. Cathepsin B launches an apoptotic exit effort upon cell death-associated disruption of lysosomes.  Cell Death Discov. 2016, 2, 16012. [Google Scholar]
50.
Nagakannan P, Islam MI, Conrad M, Eftekharpour E. Cathepsin B is an executioner of ferroptosis.  Biochim. Biophys. Acta Mol. Cell. Res. 2021, 1868, 118928. [Google Scholar]
51.
Cavaillès V, Augereau P, Rochefort H. Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells.  Proc. Natl. Acad. Sci. USA 1993, 90, 203–207. [Google Scholar]
52.
Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease.  Clin. Liver Dis. 2004, 8, 67–81. [Google Scholar]
53.
Ye HL, Zhang JW, Chen XZ, Wu PB, Chen L, Zhang G. Ursodeoxycholic acid alleviates experimental liver fibrosis involving inhibition of autophagy.  Life Sci. 2020, 242, 117175. [Google Scholar]
54.
Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid.  J. Lipid Res. 2009, 50, 1721–1734. [Google Scholar]
55.
Panzitt K, Jungwirth E, Krones E, Lee JM, Pollheimer M, Thallinger GG, et al. FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis.  J. Hepatol. 2020, 72, 1122–1131. [Google Scholar]
56.
Sasaki M, Nakanuma Y. Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis.  Dig. Dis. 2017, 35, 210–216. [Google Scholar]
57.
Scott J, Jenkins W, Smith GP, Peters TJ. Hepatic organelle pathology in primary biliary cirrhosis and the response to low-dose D-penicillamine therapy.  Clin. Sci. 1981, 60, 207–212. [Google Scholar]
58.
Fang W, Deng Z, Benadjaoud F, Yang C, Shi GP. Cathepsin B deficiency ameliorates liver lipid deposition, inflammatory cell infiltration, and fibrosis after diet-induced nonalcoholic steatohepatitis.  Transl. Res. 2020, 222, 28–40. [Google Scholar]
59.
Zanelatto ACO, Lacerda GS, Accardo CM, Rosário NFD, Silva AAD, Motta G, et al. Cathepsin B and Plasma Kallikrein Are Reliable Biomarkers to Discriminate Clinically Significant Hepatic Fibrosis in Patients with Chronic Hepatitis-C Infection.  Microorganisms 2022, 10, 1769. [Google Scholar]
60.
Manchanda M, Das P, Gahlot GPS, Singh R, Roeb E, Roderfeld M, et al. Cathepsin L and B as Potential Markers for Liver Fibrosis: Insights From Patients and Experimental Models.  Clin. Transl. Gastroenterol. 2017, 8, e99. [Google Scholar]
61.
Campden RI, Zhang Y. The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation.  Arch. Biochem. Biophys. 2019, 670, 32–42. [Google Scholar]
62.
Allaire M, Rautou PE, Codogno P, Lotersztajn S. Autophagy in liver diseases: Time for translation?  J. Hepatol. 2019, 70, 985–998. [Google Scholar]
63.
Gual P, Gilgenkrantz H, Lotersztajn S. Autophagy in chronic liver diseases: the two faces of Janus.  Am. J. Physiol. Cell. Physiol. 2017, 312, C263–C273. [Google Scholar]
64.
Hung TM, Hsiao CC, Lin CW, Lee PH. Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis.  Pathogens 2020, 9, 225. [Google Scholar]
65.
Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases.  World J. Hepatol. 2021, 13, 6–65. [Google Scholar]
66.
Mahapatra KK, Mishra SR, Behera BP, Patil S, Gewirtz DA, Bhutia SK. The lysosome as an imperative regulator of autophagy and cell death.  Cell. Mol. Life Sci. 2021, 78, 7435–7449. [Google Scholar]
67.
Khurana P, Yadati T, Goyal S, Dolas A, Houben T, Oligschlaeger Y, et al. Inhibiting Extracellular Cathepsin D Reduces Hepatic Steatosis in Sprague⁻Dawley Rats.  Biomolecules 2019, 9, 171. [Google Scholar]
68.
Orlowski GM, Colbert JD, Sharma S, Bogyo M, Robertson SA, Rock KL. Multiple Cathepsins Promote Pro-IL-1β Synthesis and NLRP3-Mediated IL-1β Activation.  J. Immunol. 2015, 195, 1685–1697. [Google Scholar]
69.
Houben T, Oligschlaeger Y, Hendrikx T, Bitorina AV, Walenbergh SMA, van Gorp PJ, et al. Cathepsin D regulates lipid metabolism in murine steatohepatitis.  Sci. Rep. 2017, 7, 3494. [Google Scholar]
70.
Yadati T, Houben T, Bitorina A, Oligschlaeger Y, Gijbels MJ, Mohren R, et al. Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice.  Front. Immunol. 2021, 12, 675535. [Google Scholar]
71.
Ding L, De Munck TJI, Oligschlaeger Y, Dos Reis IM, Verbeek J, Koek GH, et al. Myosteatosis in NAFLD patients correlates with plasma Cathepsin D.  Biomol. Concepts 2021, 12, 27–35. [Google Scholar]
72.
Walenbergh SM, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, et al.  Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention.  Sci. Rep. 2016, 6, 38278. [Google Scholar]
73.
Ke PY.  Diverse Functions of Autophagy in Liver Physiology and Liver Diseases.  Int. J. Mol. Sci. 2019, 20, 300. [Google Scholar]
74.
Gao H, Bai Y, Jia Y, Zhao Y, Kang R, Tang D, et al. Ferroptosis is a lysosomal cell death process.  Biochem. Biophys. Res. Commun. 2018, 503, 1550–1556. [Google Scholar]
75.
Aits S, Jäättelä M. Lysosomal cell death at a glance.  J. Cell Sci. 2013, 126, 1905–1912. [Google Scholar]
76.
Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease.  Hepatol. Res. 2014, 44, 1026–1036. [Google Scholar]
77.
Felbor U, Kessler B, Mothes W, Goebel HH, Ploegh HL, Bronson RT, et al. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl. Acad. Sci. USA 2002, 99, 7883–7888. [Google Scholar]
78.
Vespasiani-Gentilucci U, Gallo P, Piemonte F, Riva E, Porcari A, Vorini F, et al. Lysosomal Acid Lipase Activity Is Reduced Both in Cryptogenic Cirrhosis and in Cirrhosis of Known Etiology.  PLoS ONE 2016, 11, e0156113. [Google Scholar]
79.
Baratta F, Pastori D, Ferro D, Carluccio G, Tozzi G, Angelico F, et al. Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?  World J. Gastroenterol. 2019, 25, 4172–4180. [Google Scholar]
80.
Zhang H. Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies.  Curr. Opin. Lipidol. 2018, 29, 218–223. [Google Scholar]
81.
Starkey PM, Barrett AJ. Inhibition by alpha-macroglobulin and other serum proteins.  Biochem. J. 1973, 131, 823–831. [Google Scholar]
82.
Amaral EP, Riteau N, Moayeri M, Maier N, Mayer-Barber KD, Pereira RM, et al. Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages.  Front. Immunol. 2018, 9, 1427. [Google Scholar]
83.
Sobotič B, Vizovišek M, Vidmar R, Van Damme P, Gocheva V, Joyce JA, et al.  Proteomic Identification of Cysteine Cathepsin Substrates Shed from the Surface of Cancer Cells.  Mol. Cell. Proteomics 2015, 14, 2213–2228. [Google Scholar]
84.
Kouroumalis E, Notas G. Primary biliary cirrhosis: From bench to bedside.  World J. Gastrointest. Pharmacol. Ther. 2015, 6, 32–58. [Google Scholar]
85.
Fu HY, Bao WM, Yang CX, Lai WJ, Xu JM, Yu HY, et al. Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model.  Med. Sci. Monit. 2020, 26, e923726. [Google Scholar]
86.
Fu HY, Xu JM, Ai X, Dang FT, Tan X, Yu HY, et al. The Clostridium Metabolite P-Cresol Sulfate Relieves Inflammation of Primary Biliary Cholangitis by Regulating Kupffer Cells.  Cells 2022, 11, 3782. [Google Scholar]
87.
Gracia-Sancho J, Guixé-Muntet S. The many-faced role of autophagy in liver diseases.  J. Hepatol. 2018, 68, 593–594. [Google Scholar]
88.
Lodder J, Denaës T, Chobert MN, Wan J, El-Benna J, Pawlotsky JM, et al. Macrophage autophagy protects against liver fibrosis in mice.  Autophagy 2015, 11, 1280–1292. [Google Scholar]
89.
Mohsen S, Sobash PT, Algwaiz GF, Nasef N, Al-Zeidaneen SA, Karim NA. Autophagy Agents in Clinical Trials for Cancer Therapy: A Brief Review. Curr. Oncol. 2022, 29, 1695–1708. [Google Scholar]
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