Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration

Xu, Min; Alwahsh, Salamah Mohammad; Ramadori, Giuliano; Kollmar, Otto; Slotta, Jan E.

doi:10.1016/j.jss.2013.12.019

Cited by 15 publications

(17 citation statements)

References 28 publications

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“…Five-micrometer thick paraffin-embedded liver samples were stained with hematoxylin–eosin (H&E) as previously described [64]. Histological examination was performed by a pathologist and scientists using a light microscope with an internal digital camera [65].…”

Section: Methodsmentioning

confidence: 99%

Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome

Alwahsh

Dwyer

Forbes

et al. 2017

IJMS

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The role of the liver and the endocrine pancreas in development of hyperinsulinemia in different types of obesity remains unclear. Sedentary rats (160 g) were fed a low-fat-diet (LFD, chow 13% kcal fat), high-fat-diet (HFD, 35% fat), or HFD+ 30% ethanol+ 30% fructose (HF-EFr, 22% fat). Overnight-fasted rats were culled after one, four or eight weeks. Pancreatic and hepatic mRNAs were isolated for subsequent RT-PCR analysis. After eight weeks, body weights increased three-fold in the LFD group, 2.8-fold in the HFD group, and 2.4-fold in the HF-EFr (p < 0.01). HF-EFr-fed rats had the greatest liver weights and consumed less food during Weeks 4–8 (p < 0.05). Hepatic-triglyceride content increased progressively in all groups. At Week 8, HOMA-IR values, fasting serum glucose, C-peptide, and triglycerides levels were significantly increased in LFD-fed rats compared to that at earlier time points. The greatest plasma levels of glucose, triglycerides and leptin were observed in the HF-EFr at Week 8. Gene expression of pancreatic-insulin was significantly greater in the HFD and HF-EFr groups versus the LFD. Nevertheless, insulin: C-peptide ratios and HOMA-IR values were substantially higher in HF-EFr. Hepatic gene-expression of insulin-receptor-substrate-1/2 was downregulated in the HF-EFr. The expression of phospho-ERK-1/2 and inflammatory-mediators were greatest in the HF-EFr-fed rats. Chronic intake of both LFD and HFD induced obesity, MetS, and intrahepatic-fat accumulation. The hyperinsulinemia is the strongest in rats with the lowest body weights, but having the highest liver weights. This accompanies the strongest increase of pancreatic insulin production and the maximal decrease of hepatic insulin signaling, which is possibly secondary to hepatic fat deposition, inflammation and other factors.

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Section: Methodsmentioning

confidence: 99%

Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome

Alwahsh

Dwyer

Forbes

et al. 2017

IJMS

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“…Thus, it is reasonable to speculate that LUBAC deficiency would lower the threshold of apoptosis and render hepatocytes susceptible to apoptosis, even when exposed to minor inflammatory stimuli such as gut-derived lipopolysaccharide, which in turn leads to inflammatory cell recruitment and hepatic stellate cell activation, thereby inducing inflammation and fibrosis in the liver [16]. It is noteworthy that the expression of IL-6, which is known to play a protective role against CCl 4 -induced hepatocyte apoptosis and fibrosis [25] and is reportedly important in the regenerative response to partial hepatectomy [26,27], was upregulated in the livers of both L-SHARPIN KD and L-HOIP KD mice concomitantly with other inflammatory cytokines (Figure 2e and Figure 3d), an observation ruling out the possibility that the enhancements of hepatic apoptosis and fibrosis in these mice were mediated via impaired IL-6 expression.…”

Section: Discussionmentioning

confidence: 99%

Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

Yamamotoya

Nakatsu

Matsunaga

et al. 2017

IJMS

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Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

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“…26 Briefly, renal tissue was snap frozen in liquid nitrogen, cut into a thick- tissue was cut into a thickness of 5 µm, and hematoxylin and eosin stain (H&E) staining was done using a standard protocol. 26 Briefly, renal tissue was snap frozen in liquid nitrogen, cut into a thick- tissue was cut into a thickness of 5 µm, and hematoxylin and eosin stain (H&E) staining was done using a standard protocol.…”

Section: Immunofluorescence and Hande Staining Histology Assessmentmentioning

confidence: 99%

“…26 Approximately 100 mg of frozen tissue was TaqMan fast master mix, 0.5μL assay mix, 1μL sample, 3.5μL H2O, and the mixture was amplified in an ABI prism 7000 reaction system. 26 Approximately 100 mg of frozen tissue was TaqMan fast master mix, 0.5μL assay mix, 1μL sample, 3.5μL H2O, and the mixture was amplified in an ABI prism 7000 reaction system.…”

Section: Total Protein Extraction and Western Blot Analysismentioning

confidence: 99%

“…Immunofluorescence (IF) staining was done as previously reported. 26 Briefly, renal tissue was snap frozen in liquid nitrogen, cut into a thick- tissue was cut into a thickness of 5 µm, and hematoxylin and eosin stain (H&E) staining was done using a standard protocol. The AR of allograft was assessed by a renal pathologist in a blind fashion according to Banff criteria 27 ; the normal kidney was recorded as no AR, the allografts without evidence of AR on histology examination but having an increased CD3 positive cell counting than the normal kidney tissue were defined as subclinical rejection.…”

Section: Immunofluorescence and Hande Staining Histology Assessmentmentioning

confidence: 99%

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Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death

Garcia‐Aroz

Banan

et al. 2019

American Journal of Transplantation

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It remains controversial whether renal allografts from donation after circulatory death (DCD) have a higher risk of acute rejection (AR). In the porcine large animal kidney transplant model, we investigated the AR and function of DCD renal allografts compared to the non-DCD renal allografts and the effects of increased immunosuppression. We found that the AR was significantly increased along with elevated MHC-I expression in the DCD transplants receiving low-dose immunosuppression; however, AR and renal function were significantly improved when given high-dose immunosuppressive therapy postoperatively. Also, high-dose immunosuppression remarkably decreased the mRNA levels of ifn-g, il-6, tgf-b, il-4, and tnf-a in the allograft at day 5 and decreased serum cytokines levels of IFN-g and IL-17 at day 4 and day 5 after operation. Furthermore, Western blot analysis showed that higher immunosuppression decreased phosphorylation of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells-p65, increased phosphorylation of extracellular-signal-regulated kinase, and reduced the expression of Bcl-2-associated X protein and caspase-3 in the renal allografts. These results suggest that the DCD renal allograft seems to be more vulnerable to AR; enhanced immunosuppression reduces DCD-associated AR and improves early allograft function in a preclinical large animal model.

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Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration

Cited by 15 publications

References 28 publications

Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome

Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome

Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death

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