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Double-lobectomy in a steatotic liver transplantation rat model.

ABSTRACT: Establishing a steatotic liver transplantation animal model can be a challenging process, which requires complex microsurgical technologies. The present study established a novel rat model of stable steatotic liver transplantation for marginal liver graft research, which notably minimized the number of animals used for the experiment. Briefly, male Sprague-Dawley rats (n=90) were fed with a high-fat diet (HFD; 60%, kJ) or standard chow diet (SCD) for 8 weeks. The liver enzymes and lipid levels were assessed every week, and the degree of steatosis was determined via hematoxylin and eosin and Oil Red O staining. The results demonstrated that there were no significant differences in alanine aminotransaminase and aspartate aminotransferase levels between the SCD and HFD groups (P>0.05), whereas the level of plasma triglyceride (TG) increased by 1.76-fold in the HFD group at week 2, and progressively decreased to baseline levels by week 8. Significantly higher levels of TG were observed in the HFD group compared with the SCD group at week 2 (P<0.05). In addition, the levels of plasma glucose (P<0.05), portal insulin (P<0.05) and content of liver lipid (P<0.01) increased in the HFD group compared with the SCD group. After 6 weeks, the liver steatosis was successfully formed and stable. Consequently, a rat liver developed hepatic macrovesicular steatosis >60%, which was subsequently used for transplantation after double-lobectomy. Post-transplantation survival rates in the HFD and SCD groups were as follows: Week 1, 80 vs. 100% and 1 month, 20 vs. 100%. A total of 20 rats were not sacrificed by performing double-lobectomy for biopsy. Taken together, the results of the present study suggest that rat liver double-lobectomy may be safely applied in steatotic liver transplantation without the need to sacrifice a large number of animals.

SUBMITTER: Fan L

PROVIDER: S-EPMC7851671 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Double-lobectomy in a steatotic liver transplantation rat model.

Fan Lin L Fu Zhen Z Xiong Yan Y Ye Shaojun S Wang Yanfeng Y Peng Guizhu G Ye Qifa Q

Experimental and therapeutic medicine 20210125 3

Establishing a steatotic liver transplantation animal model can be a challenging process, which requires complex microsurgical technologies. The present study established a novel rat model of stable steatotic liver transplantation for marginal liver graft research, which notably minimized the number of animals used for the experiment. Briefly, male Sprague-Dawley rats (n=90) were fed with a high-fat diet (HFD; 60%, kJ) or standard chow diet (SCD) for 8 weeks. The liver enzymes and lipid levels w ...[more]

PMID: 33603863

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Project description:Background and aimsThis study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury.Approach and resultsHepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis.ConclusionsLack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

Project description:The present study aimed to explore whether heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) have a protective effect on liver transplantation with steatotic liver grafts in rats, and to determine the role of the intestinal microbiota in such protection. HO-1/BMMSCs were obtained by transduction of Hmox1 gene [encoding heme oxygenase (HO-1)]-encoding adenoviruses into primary rat BMMSCs. Steatotic livers were obtained by feeding rats a high-fat diet, and a model of liver transplantation with steatotic liver grafts was established. The recipients were treated with BMMSCs, HO-1/BMMSCs, or neither, via the portal vein. Two time points were used: postoperative day 1 (POD 1) and POD 7. The results showed that under the effect of HO-1/BMMSCs, the degree of steatosis in the liver grafts was significantly reduced, and the level of liver enzymes and the levels of pro-inflammatory cytokines in plasma were reduced. The effect of HO-1/BMMSCs was better than that of pure BMMSCs in the prolongation of the rats' postoperative time. In addition, HO-1/BMMSCs promoted the recovery of recipients' intestinal structure and function, especially on POD 7. The intestinal villi returned to normal, the expression of tight junction proteins was restored, and intestinal permeability was reduced on POD 7. The intestinal bacterial of the LT group showed significantly weakened energy metabolism and overgrowth. On POD 1, the abundance of Akkermansiaceae was higher. On POD 7, the abundance of Clostridiaceae increased, the level of lipopolysaccharide increased, the intestinal mucosal barrier function was destroyed, and the levels of several invasive bacteria increased. When treated with HO-1/BMMSCs, the energy metabolism of intestinal bacteria was enhanced, and on POD 1, levels bacteria that protect the intestinal mucosa, such as Desulfovibrionaceae, increased significantly. On POD 7, the changed intestinal microbiota improved lipid metabolism and increased the levels of butyrate-producing bacteria, such as Lachnospiraceae. In conclusion, HO-1/BMMSCs have protective effects on steatotic liver grafts and the intestinal barrier function of the recipients. By improving lipid metabolism and increasing the abundance of butyrate-producing bacteria, the changed intestinal microbiota has a protective effect and prolongs the recipients' survival time.

Dataset Information

Double-lobectomy in a steatotic liver transplantation rat model.

Publications

Double-lobectomy in a steatotic liver transplantation rat model.

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