scholarly journals Lack of Multidrug Resistance-associated Protein 4 Prolongs Partial Hepatectomy-induced Hepatic Steatosis

2020 ◽  
Vol 175 (2) ◽  
pp. 301-311
Author(s):  
Ajay C Donepudi ◽  
Gregory J Smith ◽  
Oladimeji Aladelokun ◽  
Yoojin Lee ◽  
Steven J Toro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multidrug Resistance ◽  
Liver Injury ◽  
Liver Regeneration ◽  
Hepatic Steatosis ◽  
Partial Hepatectomy ◽  
Knockout Mice ◽  
Tissue Loss ◽  
Hepatocyte Proliferation ◽  
Hepatic Lipid

Abstract Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter involved in the active transport of several endogenous and exogenous chemicals. Previously, we have shown that hepatic Mrp4 expression increases following acetaminophen overdose. In mice, these increases in Mrp4 expression are observed specifically in hepatocytes undergoing active proliferation. From this, we hypothesized that Mrp4 plays a key role in hepatocyte proliferation and that lack of Mrp4 impedes liver regeneration following liver injury and/or tissue loss. To evaluate the role of Mrp4 in these processes, we employed two-third partial hepatectomy (PH) as an experimental liver regeneration model. In this study, we performed PH-surgery on male wildtype (C57BL/6J) and Mrp4 knockout mice. Plasma and liver tissues were collected at 24, 48, and 72 h postsurgery and evaluated for liver injury and liver regeneration endpoints, and for PH-induced hepatic lipid accumulation. Our results show that lack of Mrp4 did not alter hepatocyte proliferation and liver injury following PH as evaluated by Ki-67 antigen staining and plasma alanine aminotransferase levels. To our surprise, Mrp4 knockout mice exhibited increased hepatic lipid content, in particular, di- and triglyceride levels. Gene expression analysis showed that lack of Mrp4 upregulated hepatic lipin1 and diacylglycerol O-acyltransferase 1 and 2 gene expression, which are involved in the synthesis of di- and triglycerides. Our observations indicate that lack of Mrp4 prolonged PH-induced hepatic steatosis in mice and suggest that Mrp4 may be a novel genetic factor in the development of hepatic steatosis.

scholarly journals Inhibition of miR-21 rescues liver regeneration after partial hepatectomy in ethanol-fed rats

2016 ◽  
Vol 311 (5) ◽  
pp. G794-G806 ◽  
Author(s):  
Egle Juskeviciute ◽  
Rachael P. Dippold ◽  
Anil N. Antony ◽  
Aditi Swarup ◽  
Rajanikanth Vadigepalli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Stellate Cell ◽  
Locked Nucleic Acid ◽  
Hepatocyte Proliferation

Liver regeneration is a clinically significant tissue repair process that is suppressed by chronic alcohol intake through poorly understood mechanisms. Recently, microRNA-21 (miR-21) has been suggested to serve as a crucial microRNA (miRNA) regulator driving hepatocyte proliferation after partial hepatectomy (PHx) in mice. However, we reported recently that miR-21 is significantly upregulated in ethanol-fed rats 24 h after PHx, despite inhibition of cell proliferation, suggesting a more complex role for this miRNA. Here, we investigate how inhibition of miR-21 in vivo affects the early phase of liver regeneration in ethanol-fed rats. Chronically ethanol-fed rats and pair-fed control animals were treated with AM21, a mixed locked nucleic acid-DNA analog antisense to miR-21 that inhibited miR-21 in vivo to undetectable levels. Liver regeneration after PHx was followed by cell proliferation marker and gene expression analysis, miRNA profiling, and cell signaling pathway analysis. Although liver regeneration was not significantly impaired by AM21 in chow-fed rats, AM21 treatment in ethanol-fed animals completely restored regeneration and enhanced PHx-induced hepatocyte proliferation to levels comparable to those of untreated or chow-fed animals. In addition, a marked deposition of α-smooth muscle actin, a marker of stellate cell activation, which was evident in ethanol-treated animals after PHx, was effectively suppressed by AM21 treatment. Gene expression analysis further indicated that suppression of stellate cell-specific profibrogenic profiles and the Notch signaling contributed to AM21-mediated rescue from deficient hepatocyte proliferation in ethanol-fed animals. Our results indicate that the impact of miR-21 balances proproliferative effects with antiproliferative profibrogenic actions in regulating distinctive regenerative responses in normal vs. disease conditions.

scholarly journals Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bernat Córdoba-Jover ◽  
Altamira Arce-Cerezo ◽  
Jordi Ribera ◽  
Montse Pauta ◽  
Denise Oró ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Regeneration ◽  
Cerium Oxide ◽  
Partial Hepatectomy ◽  
Experimental Models ◽  
Cerium Oxide Nanoparticles ◽  
Hepatic Regeneration ◽  
Oxide Nanoparticles ◽  
Acetyl Cysteine

Abstract Background and aims Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose. Methods All the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats. Results In the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo. Conclusions Our results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

scholarly journals Platelet Interactions with Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells Lead to Hepatocyte Proliferation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1243 ◽  
Author(s):  
Jeremy Meyer ◽  
Alexandre Balaphas ◽  
Pierre Fontana ◽  
Philippe Morel ◽  
Simon C. Robson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatocyte Proliferation ◽  
Liver Sinusoidal Endothelial Cells ◽  
Hepatocyte Growth

(1) Background: Platelets were postulated to constitute the trigger of liver regeneration. The aim of this study was to dissect the cellular interactions between the various liver cells involved in liver regeneration and to clarify the role of platelets. (2) Methods: Primary mouse liver sinusoidal endothelial cells (LSECs) were co-incubated with increasing numbers of resting platelets, activated platelets, or platelet releasates. Alterations in the secretion of growth factors were measured. The active fractions of platelet releasates were characterized and their effects on hepatocyte proliferation assessed. Finally, conditioned media of LSECs exposed to platelets were added to primary hepatic stellate cells (HSCs). Secretion of hepatocyte growth factor (HGF) and hepatocyte proliferation were measured. After partial hepatectomy in mice, platelet and liver sinusoidal endothelial cell (LSEC) interactions were analyzed in vivo by confocal microscopy, and interleukin-6 (IL-6) and HGF levels were determined. (3) Results: Co-incubation of increasing numbers of platelets with LSECs resulted in enhanced IL-6 secretion by LSECs. The effect was mediated by the platelet releasate, notably a thermolabile soluble factor with a molecular weight over 100 kDa. The conditioned medium of LSECs exposed to platelets did not increase proliferation of primary hepatocytes when compared to LSECs alone but stimulated hepatocyte growth factor (HGF) secretion by HSCs, which led to hepatocyte proliferation. Following partial hepatectomy, in vivo adhesion of platelets to LSECs was significantly increased when compared to sham-operated mice. Clopidogrel inhibited HGF secretion after partial hepatectomy. (4) Conclusion: Our findings indicate that platelets interact with LSECs after partial hepatectomy and activate them to release a large molecule of protein nature, which constitutes the initial trigger for liver regeneration.

scholarly journals Effect of antihypertensive agents on stellate cells during liver regeneration in rats

2003 ◽  
Vol 40 (1) ◽  
pp. 40-44 ◽  
Author(s):  
Leandra N. Z. Ramalho ◽  
Sérgio Zucoloto ◽  
Fernando S. Ramalho ◽  
Orlando de Castro-e-Silva Jr. ◽  
Fernando M. A. Corrêa
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Cell Population ◽  
Stellate Cell ◽  
Antihypertensive Agents ◽  
Stellate Cells ◽  
Tissue Loss ◽  
Hepatic Tissue ◽  
Control Group ◽  
Quiescent State

BACKGROUND: Although most studies have focused on the hepatocytes, all the hepatic cells participate in the regenerative process, among them the stellate cells. The stellate cells are mesenchymal cells involved in local neurotransmission and paracrine regulation of several liver functions. Acute hepatic tissue loss promotes the proliferation and activation of stellate cells from a quiescent state to myofibroblast-like cells. AIM: Investigate the effects of antihypertensive agents on the stellate cell population during the liver regenerative phenomenon in rats. METHODS: Adult male Wistar rats received lisinopril, losartan, bradykinin, or saline solution in a proportional volume, intraperitoneally, before and after 70% partial hepatectomy. Animals from the experimental and saline groups were sacrificed at 36 hours after partial hepatectomy. The alpha-smooth muscle actin labelled stellate cells population was counted in the periportal and pericentral zones of the liver specimen. RESULTS: The labelled stellate cells were more numerous in the control group both in the periportal and pericentral zones at 36 hours after partial hepatectomy than at the other times. The population of stellate cells was significantly lower in the losartan group and higher in the bradykinin and lisinopril groups than in the control group. CONCLUSIONS: These results suggest that losartan can inhibit and bradykinin and lisinopril can stimulate the stellate cell population during liver regeneration in rats. These cells synthesize several substances to stimulate liver regeneration.

The impact of hepatic steatosis on liver regeneration after partial hepatectomy

2013 ◽  
Vol 33 (3) ◽  
pp. 469-475 ◽  
Author(s):  
Petra G. Kele ◽  
Eric J. van der Jagt ◽  
Annette S. H. Gouw ◽  
Ton Lisman ◽  
Robert J. Porte ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatic Steatosis ◽  
Partial Hepatectomy ◽  
The Impact

scholarly journals Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse

2018 ◽  
Vol 315 (5) ◽  
pp. E735-E744 ◽  
Author(s):  
Mary Frances Lopez ◽  
Lingyun Zheng ◽  
Ji Miao ◽  
Reddy Gali ◽  
Grzegorz Gorski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Growth Factor ◽  
Hepatic Steatosis ◽  
Intrauterine Growth Restriction ◽  
Nutritional Deficiency ◽  
Growth Restriction ◽  
Newborn Mouse ◽  
Hepatic Lipid ◽  
Intrauterine Growth

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2−/−), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2−/− mice are born with hepatic steatosis. Gene expression analysis in Igf2−/− newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2−/− newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

scholarly journals Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

2002 ◽  
Vol 99 (17) ◽  
pp. 11181-11186 ◽  
Author(s):  
A. I. Su ◽  
L. G. Guidotti ◽  
J. P. Pezacki ◽  
F. V. Chisari ◽  
P. G. Schultz
Keyword(s):  
Gene Expression ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Priming Phase
Sign in / Sign up

Export Citation Format

Share Document