Dysplastic Hepatocytes Develop Nuclear Inclusions in a Mouse Model of Viral Hepatitis

Thakur, Priyanka; Lamoke, Folami; Chaffin, Joanna; Bartoli, Manuela; Lee, Jeffrey R.; Duncan, Michael B.

doi:10.1371/journal.pone.0099872

Cited by 9 publications

(9 citation statements)

References 37 publications

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“…A transgenic mouse model of hepatitis B surface antigen mediated hepatitis exhibited nuclear inclusions in murine hepatocytes and the presence of inclusions correlated with oxidative stress and proliferation . The authors did not investigate the inclusions by means of electron microscopy to show a limiting nuclear membrane.…”

Section: Discussionmentioning

confidence: 99%

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

Schwertheim

Westerwick

Jastrow

et al. 2019

The Journal of Pathology CR

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For decades, intranuclear inclusions in many normal and neoplastic cells have been considered to be mere invaginations of cytoplasm into the nucleus without any notable function or influence on disease. We investigated such inclusions in 75 specimens of hepatocellular carcinoma (HCC). In this context we demonstrate that these inclusions are true inclusions, completely closed and delimited by the nuclear membrane, containing degenerate cell organelles and lysosomal proteins. Moreover, their occurrence was positively associated with patient survival but not with tumour grade or stage. In a standardised area a mean of 124 inclusions per specimen was present in the tumorous liver tissue in contrast to 5 inclusions in the non‐tumorous adjacent section and 89% of all scrutinised HCC showed at least one membrane‐bound nuclear inclusion. Ultrastructural characterisation by transmission electron microscopy revealed degenerative materials such as residues of lysosomes, endoplasmic reticulum and Golgi apparatus within the inclusions. Due to the fact that the content of the inclusions appears to be more condensed than cytoplasm and contains fewer intact cell organelles, we assume that they are not mere invaginations of cytoplasm. Three dimensional (3D) reconstruction of isolated and immunofluorescence stained nuclei showed that the inclusions are completely located within the nucleus without any connection to the cytoplasm. The limiting membrane of the inclusions contained lamin B suggesting nuclear membrane origin. The content of the inclusions stained for the autophagy‐associated proteins p62, ubiquitin, LC3B, cathepsin B and cathepsin D. Triple immunofluorescence staining followed by 3D reconstruction revealed co‐localisation of p62, ubiquitin and LC3B in the same inclusion. Our observations uncover that these inclusions are real inclusions completely surrounded by the nucleus. We propose that the presence of autophagy‐associated proteins and proteases within the inclusions contribute to beneficial survival.

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Section: Discussionmentioning

confidence: 99%

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

Schwertheim

Westerwick

Jastrow

et al. 2019

The Journal of Pathology CR

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“…Moreover, in a rat model of STZ-induced diabetes, hyperglycaemia was associated with large glycogen deposits in renal tubular cells nine months later [ 34 ]. The presence of nuclear inclusion bodies is likely to reflect hyperglycaemia and lead to cellular damage [ 35 ]. In our study, the histopathological changes seen in the Chow_lowSTZ group were clearly juxtaposed against those changes seen in the HFD and HFD_hiSTZ groups.…”

Section: Discussionmentioning

confidence: 99%

Mouse Models of Diabetes, Obesity and Related Kidney Disease

et al. 2016

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Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice.

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“…5b). The transgenic model of HBV surface antigens exhibited nuclear inclusions in hepatocytes [56]. The fraction of nuclear inclusion localized p62 might be protected from degradation thus providing a possible explanation for similar expression levels of p62 in the livers of WT and HBs/CB1 −/− mice (Fig.…”

Section: Discussionmentioning

confidence: 86%

Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2

Irungbam

Churin

Matono

et al. 2020

Laboratory Investigation

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The endocannabinoid (EC) system has been implicated in the pathogenesis of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). With the current study we aimed to verify the modulatory effect of endocannabinoid receptor 1 (CB1)-signaling on perilipin 2 (PLIN2)-mediated lipophagy. Here, we demonstrate that a global knockout of the cannabinoid receptor 1 gene (CB1−/−) reduced the expression of the lipid droplet binding protein PLIN2 in the livers of CB1−/− and hepatitis B surface protein (HBs)-transgenic mice, which spontaneously develop hepatic steatosis. In addition, the pharmacologic activation and antagonization of CB1 in cell culture also caused an induction or reduction of PLIN2, respectively. The decreased PLIN2 expression was associated with suppressed lipogenesis and triglyceride (TG) synthesis and enhanced autophagy as shown by increased colocalization of LC3B with lysosomal-associated membrane protein 1 (LAMP1) in HBs/CB1−/− mice. The induction of autophagy was further supported by the increased expression of LAMP1 in CB1−/− and HBs/CB1−/− mice. LAMP1 and PLIN2 were co-localized in HBs/CB1−/− indicating autophagy of cytoplasmic lipid droplets (LDs) i.e., lipophagy. Lipolysis of lipid droplets was additionally indicated by elevated expression of lysosomal acid lipase. In conclusion, these results suggest that loss of CB1 signaling leads to reduced PLIN2 abundance, which triggers lipophagy. Our new findings about the association between CB1 signaling and PLIN2 may stimulate translational studies analyzing new diagnostic and therapeutic options for NAFLD.

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Dysplastic Hepatocytes Develop Nuclear Inclusions in a Mouse Model of Viral Hepatitis

Cited by 9 publications

References 37 publications

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

Mouse Models of Diabetes, Obesity and Related Kidney Disease

Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2

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