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Article ; Online: Autophagic dysfunction in the liver enhances the expression of insoluble nuclear proteins 14-3-3ζ and importin α4.

Izumi, Kousuke / Yamashina, Shunhei / Fujimura, Tsutomu / Watanabe, Sumio / Ikejima, Kenichi

2022 Volume 298, Page(s) 120491

Abstract: Aims: Autophagic dysfunction is associated with the progression of various liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, serum markers for evaluating autophagic function have not been reported. Highly insoluble nuclear ... ...

Abstract	Aims: Autophagic dysfunction is associated with the progression of various liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, serum markers for evaluating autophagic function have not been reported. Highly insoluble nuclear proteins participate in many cellular functions and are potential diagnostic markers for cancer. We performed a proteomic analysis of the hepatic nuclear insoluble fraction to identify novel autophagy-related diagnostic biomarkers. Main methods: The insoluble nuclear protein fraction was extracted from the livers of Atg7 Key findings: The levels of insoluble nuclear proteins 14-3-3ζ and importin α4 were upregulated following hepatic autophagy dysfunction and were detectable in serum. Under normal conditions, these proteins are mainly distributed in the cytoplasm, whereas autophagic dysfunction induces their translocation to the nucleus. Incubation with an autophagy inhibitor up-regulated these proteins expression in the insoluble nuclear fraction of primary hepatocytes. Treatment with EGF or insulin enhanced 14-3-3ζ expression in the nuclear insoluble fraction; in contrast, the addition of rapamycin downregulated 14-3-3ζ expression. Importin α4 expression was increased in the nuclear insoluble fraction after incubation with tunicamycin or hydrogen peroxide. Significance: Accumulation of 14-3-3ζ and importin α4 as nuclear-insoluble proteins may be associated with autophagic dysfunction. Our findings indicate that these proteins might be useful diagnostic biomarkers for liver diseases with autophagic disorders.
MeSH term(s)	14-3-3 Proteins/metabolism ; Animals ; Autophagy ; Hepatocytes/metabolism ; Karyopherins/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/metabolism ; Nuclear Proteins/metabolism ; Proteomics ; alpha Karyopherins
Chemical Substances	14-3-3 Proteins ; Karyopherins ; Nuclear Proteins ; alpha Karyopherins
Language	English
Publishing date	2022-03-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2022.120491
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Article: Autophagic dysfunction in the liver enhances the expression of insoluble nuclear proteins 14-3-3ζ and importin α4

Izumi, Kousuke / Yamashina, Shunhei / Fujimura, Tsutomu / Watanabe, Sumio / Ikejima, Kenichi

Life sciences. 2022 June 01, v. 298

2022

Abstract: Autophagic dysfunction is associated with the progression of various liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, serum markers for evaluating autophagic function have not been reported. Highly insoluble nuclear proteins ... ...

Abstract	Autophagic dysfunction is associated with the progression of various liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, serum markers for evaluating autophagic function have not been reported. Highly insoluble nuclear proteins participate in many cellular functions and are potential diagnostic markers for cancer. We performed a proteomic analysis of the hepatic nuclear insoluble fraction to identify novel autophagy-related diagnostic biomarkers. The insoluble nuclear protein fraction was extracted from the livers of Atg7F/F, Atg7F/F:alb-Cre (hepatocyte-specific autophagy-deficient mice), C57BL/6 J, and KKAʸ (NAFLD model) mice. Proteins were separated by two-dimensional electrophoresis and visualized by silver staining. Protein spots were identified using mass spectrometry. The localization of proteins in hepatocytes was verified by immunofluorescence using a confocal microscope. The levels of insoluble nuclear proteins 14-3-3ζ and importin α4 were upregulated following hepatic autophagy dysfunction and were detectable in serum. Under normal conditions, these proteins are mainly distributed in the cytoplasm, whereas autophagic dysfunction induces their translocation to the nucleus. Incubation with an autophagy inhibitor up-regulated these proteins expression in the insoluble nuclear fraction of primary hepatocytes. Treatment with EGF or insulin enhanced 14-3-3ζ expression in the nuclear insoluble fraction; in contrast, the addition of rapamycin downregulated 14-3-3ζ expression. Importin α4 expression was increased in the nuclear insoluble fraction after incubation with tunicamycin or hydrogen peroxide. Accumulation of 14-3-3ζ and importin α4 as nuclear-insoluble proteins may be associated with autophagic dysfunction. Our findings indicate that these proteins might be useful diagnostic biomarkers for liver diseases with autophagic disorders.
Keywords	autophagy ; biomarkers ; blood serum ; cytoplasm ; fatty liver ; fluorescent antibody technique ; hepatocytes ; hydrogen peroxide ; importins ; insulin ; liver ; mass spectrometry ; models ; proteomics ; rapamycin ; silver ; tunicamycin ; two-dimensional gel electrophoresis
Language	English
Dates of publication	2022-0601
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2022.120491
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Article: Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA

Someya, Shunin / Uchiyama, Akira / Arai, Kumiko / Kon, Kazuyoshi / Yamashina, Shunhei / Watanabe, Sumio / Ikejima, Kenichi

Biochemical and biophysical research communications. 2022 Jan. 15, v. 588

2022

Abstract: Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of ... ...

Abstract	Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of polyinosinic-polycytidylic acid (poly I:C) for 24 weeks developed overt cholangitis with positive serum anti-mitochondria-M2 antibody, whereas male mice showed minimal pathological changes without induction in autoantibody. Poly I:C induced hepatic inflammatory cytokines and type-I interferons predominantly in females. Hepatic expression levels of toll-like receptor (TLR) 3 and melanoma differentiation-associated protein (MDA) 5 were equivalent in both genders; however, both mRNA and protein levels of retinoic acid-inducible gene (RIG)-I were nearly doubled in female livers. Following 4-week injections of poly I:C, not only hepatic RIG-I, but also TLR3 and MDA5 showed female-predominance. Moreover, hepatic RIG-I levels were 25% lower in ovariectomized mice, whereas supplementation of 17 β-estradiol enhanced hepatic RIG-I expression, as well as cytokine induction. These results clearly indicate that hepatic RIG-I expression is potentiated by estrogen, and triggers gender-dependent hepatic innate immune response against double-stranded RNA, which most likely play a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.
Keywords	autoantibodies ; blood serum ; cytokines ; double-stranded RNA ; estrogens ; females ; gender differences ; genes ; humans ; innate immunity ; males ; melanoma ; mice ; ovariectomy ; pathogenesis ; polyinosinic-polycytidylic acid ; research
Language	English
Dates of publication	2022-0115
Size	p. 90-96.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.12.011
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Article ; Online: Nonalcoholic fatty liver disease and alcohol-related liver disease: From clinical aspects to pathophysiological insights.

Ikejima, Kenichi / Kon, Kazuyoshi / Yamashina, Shunhei

Clinical and molecular hepatology

2020 Volume 26, Issue 4, Page(s) 728–735

Abstract: Two major causes of steatohepatitis are alcohol and metabolic syndrome. Although the underlying causes of alcoholrelated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) differ, there are certain ... ...

Abstract	Two major causes of steatohepatitis are alcohol and metabolic syndrome. Although the underlying causes of alcoholrelated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) differ, there are certain similarities in terms of the mode of disease progression and underlying pathophysiological mechanisms. Further, excessive alcohol consumption is often seen in patients with metabolic syndrome, and alcoholic hepatitis exacerbation by comorbidity with metabolic syndrome is an emerging clinical problem. There are certain ethnic differences in the development of both NAFLD and ALD. Especially, Asian populations tend to be more susceptible to NAFLD, and genetic polymorphisms in patatin-like phospholipase domain-containing 3 (PNPLA3) play a key role in both NAFLD and ALD. From the viewpoint of pathophysiology, cellular stress responses, including autophagy and endoplasmic reticulum (ER) stress, are involved in the development of cellular injury in steatohepatitis. Further, gutderived bacterial products and innate immune responses in the liver most likely play a profound role in the pathogenesis of both ALD and NASH. Though the recent progress in the treatment of viral hepatitis has reduced the prevalence of viral-related development of hepatocellular carcinoma (HCC), non-viral HCC is increasing. Alcohol and metabolic syndrome synergistically exacerbate progression of steatohepatitis, resulting in carcinogenesis. The gut-liver axis is a potential therapeutic and prophylactic target for steatohepatitis and subsequent carcinogenesis.
MeSH term(s)	Carcinoma, Hepatocellular ; Humans ; Liver Neoplasms ; Metabolic Syndrome ; Non-alcoholic Fatty Liver Disease
Language	English
Publishing date	2020-10-01
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2672560-5
ISSN	2287-285X ; 2287-2728
ISSN (online)	2287-285X
ISSN	2287-2728
DOI	10.3350/cmh.2020.0202
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Article ; Online: Benefit of an action camera in endoscopy education for medical students under COVID-19.

Uchiyama, Akira / Yamashina, Shunhei / Sato, Toshifumi / Sakuma, Satoshi / Tomiki, Yuichi / Isayama, Hiroyuki / Nagahara, Akihito / Ikejima, Kenichi

BMC medical education

2023 Volume 23, Issue 1, Page(s) 693

Abstract: Background: Endoscopy is an important form of clinical gastroenterology education because it gives students the opportunity to learn about diagnosis procedures and even treatment. During the COVID-19 pandemic, medical students were observed from outside ...

Abstract	Background: Endoscopy is an important form of clinical gastroenterology education because it gives students the opportunity to learn about diagnosis procedures and even treatment. During the COVID-19 pandemic, medical students were observed from outside the endoscopy room due to the risk of airborne infection. In this study, we investigated the efficacy of combining endoscopy education with doctor's-eye-view videos of the procedure obtained using live-action cameras (GoPro®). Methods: From February to May 2021, endoscopists wore GoPro Hero8 cameras on their heads to display a doctor's-eye view video outside the room. The efficacy of the GoPro videos in combination with endoscopic monitoring was evaluated by 15 participating medical students. The participants rated the efficacy on a 5-point scale and commented on the positive and negative points. Results: A total of 78.6% of participants evaluated the GoPro as good; 57.2% answered that it increased their understanding, with 71.4% stating that it increased their understanding of procedures in particular. A total of 85.7% of the students answered that their interest in endoscopy had increased, and 85.7% evaluated the benefit of the GoPro videos as good. In addition, 64.3% answered that the method was effective in preventing COVID-19 infection. Education using GoPro videos enabled students to feel as if they were conducting the endoscopy themselves and enabled them to concentrate on learning. Conclusions: Practical endoscopic education using a GoPro is an effective educational tool that not only increases understanding of endoscopic practice but also stimulates students' interest and awareness of their future as doctors.
MeSH term(s)	Humans ; Students, Medical ; Pandemics/prevention & control ; COVID-19/prevention & control ; Educational Status ; Endoscopy
Language	English
Publishing date	2023-09-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2044473-4
ISSN	1472-6920 ; 1472-6920
ISSN (online)	1472-6920
ISSN	1472-6920
DOI	10.1186/s12909-023-04702-6
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Article ; Online: Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA.

Someya, Shunin / Uchiyama, Akira / Arai, Kumiko / Kon, Kazuyoshi / Yamashina, Shunhei / Watanabe, Sumio / Ikejima, Kenichi

Biochemical and biophysical research communications

2021 Volume 588, Page(s) 90–96

Abstract	Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of polyinosinic-polycytidylic acid (poly I:C) for 24 weeks developed overt cholangitis with positive serum anti-mitochondria-M2 antibody, whereas male mice showed minimal pathological changes without induction in autoantibody. Poly I:C induced hepatic inflammatory cytokines and type-I interferons predominantly in females. Hepatic expression levels of toll-like receptor (TLR) 3 and melanoma differentiation-associated protein (MDA) 5 were equivalent in both genders; however, both mRNA and protein levels of retinoic acid-inducible gene (RIG)-I were nearly doubled in female livers. Following 4-week injections of poly I:C, not only hepatic RIG-I, but also TLR3 and MDA5 showed female-predominance. Moreover, hepatic RIG-I levels were 25% lower in ovariectomized mice, whereas supplementation of 17 β-estradiol enhanced hepatic RIG-I expression, as well as cytokine induction. These results clearly indicate that hepatic RIG-I expression is potentiated by estrogen, and triggers gender-dependent hepatic innate immune response against double-stranded RNA, which most likely play a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.
MeSH term(s)	Animals ; Autoantibodies/blood ; Cholangitis/blood ; Cholangitis/immunology ; Cholangitis/pathology ; Cytokines/metabolism ; DEAD Box Protein 58/metabolism ; Estrogens/pharmacology ; Female ; Interferon-Induced Helicase, IFIH1/metabolism ; Liver/metabolism ; Male ; Mice, Inbred C57BL ; Poly I-C/adverse effects ; RNA, Double-Stranded/adverse effects ; Receptors, Pattern Recognition/metabolism ; Sex Characteristics ; Toll-Like Receptor 3/metabolism ; Mice
Chemical Substances	Autoantibodies ; Cytokines ; Estrogens ; RNA, Double-Stranded ; Receptors, Pattern Recognition ; Toll-Like Receptor 3 ; DEAD Box Protein 58 (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13) ; Poly I-C (O84C90HH2L)
Language	English
Publishing date	2021-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.12.011
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Article ; Online: Carbohydrate-deficient transferrin is a sensitive marker of alcohol consumption in fatty liver disease.

Morinaga, Maki / Kon, Kazuyoshi / Uchiyama, Akira / Fukada, Hiroo / Fukuhara, Kyoko / Yaginuma, Reiko / Nakadera, Eisuke / Yamashina, Shunhei / Ikejima, Kenichi

Hepatology international

2022 Volume 16, Issue 2, Page(s) 348–358

Abstract: Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated/related liver disease (ALD) with metabolic syndrome is increasing globally. Metabolic syndrome and excessive alcohol consumption synergically exacerbate liver ... ...

Abstract	Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated/related liver disease (ALD) with metabolic syndrome is increasing globally. Metabolic syndrome and excessive alcohol consumption synergically exacerbate liver pathologies; therefore, drinking-specific serum markers unaffected by liver injury or metabolic syndrome are essential for assessing alcohol consumption. We evaluated the ratio of carbohydrate-deficient transferrin to total transferrin (%CDT) in patients with fatty liver disease, particularly focusing on its correlation with metabolic factors (UMIN000033550). Methods: A total of 120 patients with fatty liver disease, including ALD and NAFLD, were screened for alcohol misuse using the Alcohol Use Disorders Identification Test. Associations of metabolic syndrome-related factors and hepatic steatosis/liver stiffness with drinking markers, such as %CDT, gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV), were assessed using multiple linear regression analyses. Results: %CDT significantly increased with 3-4 drinks/day. The optimal cutoff value for identifying non- to light drinkers was 1.78% (sensitivity, 71.8%; specificity, 83.7%; and area under the receiver operating characteristic curve [AUROC], 0.851), which was significantly higher than that for GGT. The cutoff value for identifying heavy drinkers was 2.08% (sensitivity, 65.5%; specificity, 86.8%; and AUROC, 0.815). Multiple regression analysis revealed that this proportion was negatively correlated with body mass index, whereas GGT and MCV were influenced by multiple factors involved in liver injury and dyslipidemia. Conclusions: %CDT showed a strong correlation with alcohol consumption, independent of liver damage, steatosis/stiffness, or metabolic syndrome-related factors, indicating that it is a useful drinking marker for the accurate diagnosis of NAFLD and ALD.
MeSH term(s)	Alcohol Drinking/adverse effects ; Alcoholism ; Biomarkers ; Humans ; Metabolic Syndrome/diagnosis ; Non-alcoholic Fatty Liver Disease/diagnosis ; Transferrin/analogs & derivatives ; Transferrin/analysis ; gamma-Glutamyltransferase
Chemical Substances	Biomarkers ; Transferrin ; carbohydrate-deficient transferrin ; gamma-Glutamyltransferase (EC 2.3.2.2)
Language	English
Publishing date	2022-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2270316-0
ISSN	1936-0541 ; 1936-0533
ISSN (online)	1936-0541
ISSN	1936-0533
DOI	10.1007/s12072-022-10298-8
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Article: Hepatic steatosis and skeletal muscle alterations during the COVID-19 lockdown in a cohort of patients with chronic liver disease in Japan.

Uchiyama, Akira / Kon, Kazuyoshi / Sakuma, Satoshi / Sato, Toshifumi / Morinaga, Maki / Fukada, Hiroo / Yamagata, Hisafumi / Yaginuma, Reiko / Fukuhara, Kyoko / Yamashina, Shunhei / Nojiri, Shuko / Ikejima, Kenichi

Hepatology research : the official journal of the Japan Society of Hepatology

2023 Volume 54, Issue 3, Page(s) 272–283

Abstract: Aim: Following the coronavirus disease outbreak, a state of public emergency was declared worldwide, which enforced lifestyle changes. This study therefore aimed to investigate the changes in lifestyle, body composition, hepatic steatosis, and fibrosis ... ...

Abstract	Aim: Following the coronavirus disease outbreak, a state of public emergency was declared worldwide, which enforced lifestyle changes. This study therefore aimed to investigate the changes in lifestyle, body composition, hepatic steatosis, and fibrosis in patients with chronic liver disease (CLD) under lockdown. Methods: During the lockdown period, 1344 patients with CLD answered a lifestyle questionnaire. In 298 patients, body composition and liver stiffness measure (LSM)/controlled attenuation parameter (CAP) were analyzed by InBody and FibroScan, respectively, and serial data were obtained in 137 patients. Results: More than half of the CLD patients answered decreases in physical activity and frequency of outings during lockdown, while diet was less affected. Overall, 58% of patients showed elevations in CAP values, which were not different statistically over time. Women, but not men, were more likely to increase CAP values during lockdown. Neither LSM nor serum fibrosis markers were elevated chronologically during lockdown. In men, body mass index (BMI), body fat percentage, and visceral fat area (VFA) were significantly increased, whereas in women, lower-limb muscle mass was significantly decreased. Patients with decreased SMI showed elevations in CAP and VFA values, and patients who exercised less showed increases in BMI. Conclusion: In response to lockdown, men tended to increase body fat but the degree of hepatic steatosis was less affected, while women were more likely to exacerbate hepatic steatosis with skeletal muscle loss among CLD patients. Gender-specific approaches need to be established for management of CLD patients to avoid exacerbation or comorbidity of steatotic liver disease.
Language	English
Publishing date	2023-11-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1387041-5
ISSN	1386-6346 ; 0928-4346
ISSN	1386-6346 ; 0928-4346
DOI	10.1111/hepr.13981
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Article ; Online: Aging exacerbates high-fat diet-induced steatohepatitis through alteration in hepatic lipid metabolism in mice.

Ishizuka, Kei / Kon, Kazuyoshi / Lee-Okada, Hyeon-Cheol / Arai, Kumiko / Uchiyama, Akira / Yamashina, Shunhei / Yokomizo, Takehiko / Ikejima, Kenichi

Journal of gastroenterology and hepatology

2020 Volume 35, Issue 8, Page(s) 1437–1448

Abstract: Background and aim: Aging is an independent risk factor for the progression of non-alcoholic steatohepatitis. Here, we investigated the role of age-related alterations in fatty acid metabolism in dietary steatohepatitis using lipidomics analysis.: ... ...

Abstract	Background and aim: Aging is an independent risk factor for the progression of non-alcoholic steatohepatitis. Here, we investigated the role of age-related alterations in fatty acid metabolism in dietary steatohepatitis using lipidomics analysis. Methods: Male 8-week and 55-week-old C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks. The quality and quantity of lipid molecular species in the liver were evaluated using the lipidomics approach. Results: Elder mice fed an HFD developed more severe steatohepatitis than young mice. Oxidative stress and inflammatory cytokines in the liver were exacerbated following HFD feeding in elder mice compared with young mice. In elder mice, de novo fatty acid synthesis was promoted, whereas β oxidation was blunted following HFD feeding, and lipid secretion from the liver was reduced. The expression of sirtuin 1 was not only reduced with age as expected but also significantly decreased due to intake of HFD. In the lipidomics analysis, the concentrations of diacylglycerol and TAG molecular species containing monounsaturated fatty acids were markedly increased following HFD feeding in elder mice compared with young mice. In contrast, the concentration of phosphatidylethanolamine and phosphatidylcholine molecular species containing polyunsaturated fatty acids were remarkably decreased following HFD feeding in elder mice compared with young mice, and the expression of fatty acid desaturase was blunted. Conclusions: Aging-dependent alterations in lipid metabolism under excessive lipid supply most likely enhance hepatic lipotoxicity, thereby exacerbating metabolic steatohepatitis in elderly.
MeSH term(s)	Aging/metabolism ; Animals ; Diet, High-Fat/adverse effects ; Diglycerides/metabolism ; Disease Progression ; Fatty Acids, Monounsaturated/metabolism ; Fatty Acids, Unsaturated/metabolism ; Fatty Liver/etiology ; Fatty Liver/metabolism ; Lipid Metabolism ; Liver/metabolism ; Male ; Mice, Inbred C57BL ; Oxidative Stress ; Phosphatidylcholines/metabolism ; Phosphatidylethanolamines/metabolism ; Sirtuin 1/metabolism
Chemical Substances	Diglycerides ; Fatty Acids, Monounsaturated ; Fatty Acids, Unsaturated ; Phosphatidylcholines ; Phosphatidylethanolamines ; phosphatidylethanolamine (39382-08-6) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2020-02-17
Publishing country	Australia
Document type	Journal Article
ZDB-ID	632882-9
ISSN	1440-1746 ; 0815-9319
ISSN (online)	1440-1746
ISSN	0815-9319
DOI	10.1111/jgh.15006
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Article: Cathepsin L-deficiency enhances liver regeneration after partial hepatectomy

Sato, Toshifumi / Ikejima, Kenichi / Izumi, Kosuke / Koike, Masato / Peters, Christoph / Ueno, Takashi / Watanabe, Sumio / Yamashina, Shunhei

Life sciences. 2019 Mar. 15, v. 221

2019

Abstract: Cathepsin L (Ctsl) plays a pivotal role in lysosomal and autophagic proteolysis. Previous investigations revealed that partial hepatectomy (PH) decreases biosynthesis of cathepsins in liver, followed by suppression of lysosomal and autophagic proteolysis ...

Abstract	Cathepsin L (Ctsl) plays a pivotal role in lysosomal and autophagic proteolysis. Previous investigations revealed that partial hepatectomy (PH) decreases biosynthesis of cathepsins in liver, followed by suppression of lysosomal and autophagic proteolysis during liver regeneration. Conversely, it was reported that autophagy-deficiency suppressed liver regeneration. Thus, the purpose of this study is to determine if Ctsl deficiency affects liver regeneration after PH.70% of PH was performed in male Ctsl-deficient mice (Ctsl−/−) and wild-type littermates (Ctsl +/+) after PH. Mice were sacrificed and wet weight of the whole remaining liver was measured. Bromodeoxyuridine (BrdU)-immunostaining of liver sections was performed. Expression of cyclin D1, p62, LC-3, Nrf2, cleaved-Notch1, Hes1 was evaluated by western blot analysis. NQO1 mRNA expression was measured by realtime-PCR.After a 70% of PH, the liver mass was significantly restored within 5 days in Ctsl−/− mice compared to wild-type. Ctsl-deficiency enhanced the increases in both the rate of BrdU-positive cells and cyclin D1 expression after PH more than wild-type mice. On the other hand, Ctsl-deficiency upregulated p62, cleaved-Notch1 and Hes1 expression after PH. Moreover, the protein level of Nrf2 in the nucleus and mRNA expression of NQO1 in the liver after PH was also up-regulated in Ctsl−/− mice.These findings suggest that accumulation of p62 due to loss of Ctsl plays an important role in liver regeneration through activation of Nrf2-Notch1 signaling. Taken together, Ctsl might be a new therapeutic target on disorder of liver regeneration.
Keywords	biosynthesis ; cathepsins ; cyclins ; gene expression ; gene expression regulation ; hepatectomy ; liver ; liver diseases ; liver regeneration ; males ; messenger RNA ; mice ; protein content ; proteolysis ; Western blotting
Language	English
Dates of publication	2019-0315
Size	p. 293-300.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2019.02.040
Database	NAL-Catalogue (AGRICOLA)

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In stock of ZB MED Cologne/Königswinter

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