Short Term Feeding of a High Fat Diet Exerts an Additive Effect on Hepatocellular Damage and Steatosis in Liver-Specific PTEN Knockout Mice

Shearn, Colin T.; Mercer, Kelly E.; Orlicky, David J.; Hennings, Leah; Smathers-McCullough, Rebecca L.; Stiles, Bangyan L.; Ronis, Martin J. J.; Petersen, Dennis R.

doi:10.1371/journal.pone.0096553

Cited by 25 publications

(31 citation statements)

References 53 publications

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“…Stress and oxidative stress all are contributing to hepatocellular dysfunction. This report combined with previous reports also provides additional evidence that oxidative stress is an ongoing active process in NASH continuing from simple steatosis during early stages 30 throughout the course of the disease and suggests that the use of adjuvant therapeutics that target oxidative stress may still have some benefit in end stage liver disease.…”

Section: Discussionsupporting

confidence: 74%

“…Importantly, neutrophil infiltration corresponded to areas where increases in lipid peroxidation are evident. Decreased glutathione S-transferase activity is frequently identified with chronic inflammation and oxidative stress 19,30 . To determine the effects of fNASH/nfNASH on GST activity, enzyme activity assays were performed using 1-chloronitrobenzene (CDNB) as a substrate.…”

Section: Resultsmentioning

confidence: 99%

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Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Shearn

Saba

Roede

et al. 2017

Free Radical Biology and Medicine

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Objective In the liver, a contributing factor in the pathogenesis of non-alcoholic fatty liver disease is oxidative stress leading to the accumulation of highly reactive electrophilic α/β unsaturated aldehydes. The objective of this study was to determine if significant differences were evident when evaluating carbonylation in human end-stage fatty nonalcoholic steatohepatitis (fNASH) compared to end-stage nonfatty NASH (nfNASH). Methods Using hepatic tissue obtained from healthy humans and patients diagnosed with end stage nfNASH or fNASH, overall carbonylation was assessed by immunohistochemistry (IHC) and LC-MS/MS followed by bioinformatics. Results Picrosirius red staining revealed extensive fibrosis in both fNASH and nfNASH which corresponded with increased reactive aldehyde staining. Although significantly elevated when compared to normal hepatic tissue, no significant differences in overall carbonylation and fibrosis were evident when comparing fNASH with nfNASH. Examining proteins that are critical for anti-oxidant defense revealed elevated expression of thioredoxin, thioredoxin interacting protein, glutathione S-transferase p1 and mitochondrial superoxide dismutase in human NASH. As important, using immunohistochemistry, significant colocalization of the aforementioned proteins occurred in cytokeratin 7 positive cells indicating that they are part of the ductular reaction. Expression of catalase and Hsp70 decreased in both groups when compared to normal human liver. Mass spectrometric analysis revealed a total of 778 carbonylated proteins. Of these, 194 were common to all groups, 124 unique to tissue prepared from healthy individuals, 357 proteins exclusive to NASH, 124 proteins distinct to samples from patients with fNASH and 178 unique to nfNASH. Using functional enrichment analysis of hepatic carbonylated proteins revealed a propensity for increased carbonylation of proteins regulating cholesterol and Huntington’s disease related pathways occurred in nfNASH. Examining fNASH, increased carbonylation was evident in proteins regulating Rho cytoskeletal pathways, nicotinic acetylcholine receptor signaling and chemokine/cytokine inflammatory pathways. Using LC-MS/MS analysis and trypsin digests, sites of carbonylation were identified on peptides isolated from vimentin, endoplasmin and serum albumin in nfNASH and fNASH respectively. Conclusions These results indicate that cellular factors regulating mechanisms of protein carbonylation may be different depending on pathological diagnosis of NASH. Furthermore these studies are the first to use LC-MS/MS analysis of carbonylated proteins in human NAFLD and explore possible mechanistic links with end stage cirrhosis due to fatty liver disease and the generation of reactive aldehydes.

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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Shearn

Saba

Roede

et al. 2017

Free Radical Biology and Medicine

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“…As reported by Shearn et al, an HF diet can enhance hepatic inflammation in Pten Δhep mice. Here, we demonstrated further that fat overload promoted liver fibrosis as well as tumor growth in Pten Δhep mice, which were not examined in the study by Shearn et al . This is because the duration of the HF diet was longer in our study (40 weeks vs 6 weeks).…”

Section: Discussionsupporting

confidence: 57%

Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high‐fat diet

et al. 2019

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Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH‐mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH‐related liver cirrhosis and HCC. In the present study, a steatohepatitis‐related HCC model, hepatocyte‐specific phosphatase and tensin homolog (Pten)‐deficient (Pten Δhep) mice were fed a high‐fat (HF) diet with/without ezetimibe. In the standard‐diet group, ezetimibe did not reduce the development of liver tumors in Pten Δhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF‐positive cells and vascular endothelial cells in the tumors of Pten Δhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in Pten Δhep mice on the HF diet. Tumor cells were highly proliferative with HF‐diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in Pten Δhep mice with hypercholesterolemia.

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“…Second, direct interaction between LPIN1 and transcription factors (PPAR α , PGC-1 α ) amplifies the hepatic PGC-1 α /PPAR α signaling in steatosis-related gene expression [40]. Indeed, 8 steatosis-related genes [41] of the metabolic pathways were recognized to be transcriptionally induced by LPIN1 in our experiments. Members of long chain acyl-CoA synthetase (ACSL) family (ACSL1, ACSL3, ACSL4, and ACSL6) dramatically prevailed in these genes.…”

Section: Discussionmentioning

confidence: 81%

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

Guo

Wang

et al. 2017

BioMed Research International

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Circular RNAs (circRNAs) exhibit a wide range of physiological and pathological activities. To uncover their role in hepatic steatosis, we investigated the expression profile of circRNAs in HepG2-based hepatic steatosis induced by high-fat stimulation. Differentially expressed circRNAs were subjected to validation using QPCR and functional analyses using principal component analysis, hierarchical clustering, target prediction, gene ontology (GO), and pathway annotation, respectively. Bioinformatic integration established the circRNA-miRNA-mRNA regulatory network so as to identify the mechanisms underlying circRNAs' metabolic effect. Here we reported that hepatic steatosis was associated with a total of 357 circRNAs. Enrichment of transcription-related GOs, especially GO: 0006355, GO: 004589, GO: 0045944, GO: 0045892, and GO: 0000122, demonstrated their specific actions in transcriptional regulation. Lipin 1 (LPIN1) was recognized to mediate the transcriptional regulatory effect of circRNAs on metabolic pathways. circRNA-miRNA-mRNA network further identified the signaling cascade of circRNA_021412/miR-1972/LPIN1, which was characterized by decreased level of circRNA_021412 and miR-1972-based inhibition of LPIN1. LPIN1-induced downregulation of long chain acyl-CoA synthetases (ACSLs) expression finally resulted in the hepatosteatosis. These findings identify circRNAs to be important regulators of hepatic steatosis. Transcription-dependent modulation of metabolic pathways may underlie their effects, partially by the circRNA_021412/miR-1972/LPIN1 signaling.

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Short Term Feeding of a High Fat Diet Exerts an Additive Effect on Hepatocellular Damage and Steatosis in Liver-Specific PTEN Knockout Mice

Cited by 25 publications

References 53 publications

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high‐fat diet

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

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