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Leptin repletion and food restriction improve glucose tolerance, insulin sensitivity and hepatic steatosis in ob/ob mice. (a) Graph representing the evolution of blood glucose concentrations (mg/dl) over time after i.p. injection of glucose (1.5 g/kg body weight) on 4 h-fasted animals. (b) Graph representing the evolution of blood glucose concentrations (mg/dl) at the indicated time points after insulin (0.5 U/kg body weight) injected i.p. after overnight fasting. Mean glucose values obtained in lean mice (open lozenge), ob/ob mice (black square), pair-fed ob/ob mice (open square/dotted line) and leptin-repleted (250 g/kg twice daily) ob/ob mice (grey square). (c) Total lipid content was determined on anterior lobes excised at the time of PH and expressed as mg of lipid by 100 mg of wet liver (means.d.) in minimum five mice per group. Data are presented for lean mice (open bar), ob/ob mice (black bar), ob/ob mice receiving leptin 250 g/kg i.p. twice daily (grey bar) or pair-fed and (hatched bar) for 3 weeks prior to PH. *P<0.5, **P<0.01 and ***P<0.001 compared to lean livers, &&P<0.01 and &&&P<0.001 compared to ob/ob livers.Download Power Point slide (254 KB)
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Liver regeneration after partial hepatectomy (PH) is impaired in leptin-deficient ob/ob mice. Here, we tested whether exogenous leptin and/or correction of the obese phenotype (by food restriction or long-term leptin administration) would rescue hepatocyte proliferation and whether the hepatic progenitor cell compartment was activated in leptin-def...
Contexts in source publication
Context 1
... feeding and, to a greater extent, long- term leptin administration were associated with decreased fasting blood glucose concentrations and improvement of the metabolic syndrome. This was assessed in vivo by a significant amelioration of glucose tolerance in response to i.p. glucose load and normalisation of blood glucose curves after i.p. insulin challenge (Figure 5a and b). Both leptin treatment and pair feeding induced a clearance of steatosis as demonstrated on histological sections and by the reduction of hepatic lipid content (Figure 5c). ...
Context 2
... was assessed in vivo by a significant amelioration of glucose tolerance in response to i.p. glucose load and normalisation of blood glucose curves after i.p. insulin challenge (Figure 5a and b). Both leptin treatment and pair feeding induced a clearance of steatosis as demonstrated on histological sections and by the reduction of hepatic lipid content (Figure 5c). Liver regeneration in response to 55% PH was examined in long-term leptin treated and pair-fed ob/ob mice (with or without leptin injections at the time of PH). ...
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Objective
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Citations
... Les mécanismes précis par lesquels ces facteurs interagissent pour contribuer à une instabilité génomique et au développement tumoral ne sont pas entièrement élucidés. Cependant, on sait que l'accumulation de lipides a un effet délétère sur la prolifération des hépatocytes [8,9]. Ainsi, chez les personnes ayant un foie stéatosique, les hépatocytes expriment des marqueurs de sénescence, tels que la protéine P21, un raccourcissement des télomères et de nombreux dommages à l'ADN [10]. ...
... In contrast with the study of Uriarte et al., we did not find any differences in Pcna at the mRNA level (Fig. 6G). After PH, liver mass recovery is often used as a regeneration index [18,19]. It is however a rough estimate based on the wet weight that assumes removal of exactly 70% of the liver in all cases, and does not consider unrelated causes of liver mass gain although phenomena such as steatosis and hepatocyte hypertrophy are associated with regeneration. ...
Background. Postresectional liver failure (PLF) is a dreaded complication after extended liver resection. Post-operative hyperbilirubinemia suggests that impaired hepatobiliary transport with intrahepatic accumulation of harmful cholephiles plays an etiological role. Bile salts serve dual roles as signaling molecules engaged in liver regeneration after partial hepatectomy (PH) and biological detergents.
Aim. In this study we tested the hypothesis that excessive accumulation of bile salts in the regenerating liver results in PLF.
Methods. Twelve weeks old male C57BL6/J mice were subjected to 70% PH and post-operatively challenged with a diet supplemented with cholic acid (CA, 0.5 or 1.0%; n=5-6 per group) or a control diet. After 48 hours mice were sacrificed, and liver injury, secretory function, and regenerative indices were assessed.
Results. Mice fed a 1.0% CA diet displayed more pronounced weight loss following PH and had a deranged post-operative glucose course. Liver injury (aminotransferase elevations) and impaired hepatobiliary transport function (hyperbilirubinemia) were apparent in the group fed a 1.0% CA diet, but not in animals fed a 0.5% CA diet. No differences in liver mass recovery were observed among groups. However, the percentage of hepatocytes staining positive for the proliferation marker Ki-67 were reduced in mice receiving a 1.0% CA diet relative to animals fed a 0.5% CA diet. PH-induced expression of key factors involved in cell cycle progression (e.g. Foxm1b, Cdc25b) was abrogated in the 1.0% CA group.
Conclusion. A postresectional challenge with a 1.0% CA diet induces signs of liver injury and defective liver regeneration. A longer duration of the dietary challenge and/or secondary hits may further improve the model. Once validated, it can be used to evaluate pharmaceutical strategies to prevent or treat PLF.
... Considering that an injury in the liver is the first step required to trigger its regeneration, the most abundant results in this field come from studies conducted in rodent animal models either subjected to two-thirds partial hepatectomy (PHx) [262] or those of chronic injury after CCl 4 administration at hepatotoxic concentrations [263] or dietary modifications [264,265]. In this context, it has been reported that the ob/ob mice model showing NAFLD exhibited an impaired liver regeneration after PHx or toxic damage compared to the controls [266][267][268]. This impairment manifests itself with a compromised and delayed DNA synthesis, mitosis and a nonproliferative hepatocyte phenotype. ...
... Interestingly, although liver steatosis is not crucial for the impairment of liver regeneration, studies reported that transient hepatic adipogenesis is a specifically regulated step of the regenerative process. Moreover, supraphysiological leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration in wild-type mice [274]; notwithstanding, leptin supplementation in ob/ob mice to rescue the regenerative response showed discrepancies [266,267]. This could be explained by the origin of the liver damage, the animal model phenotype or the previous liver status. ...
Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
... Nonetheless, leptin replacement restored TNFα and IL-6 release and induced cyclin D1, suggesting that leptin may play a central role in the interaction between cell cycle regulators and lipid metabolism [77]. A conflicting result arises from the fact that leptin supplementation improved hepatic division, but did not reduce the onset of liver failure [78,79]. In addition, intraperitoneal injection of leptin in wild type mice with no obesity increased mitotic counts during liver regeneration [78]. ...
... A conflicting result arises from the fact that leptin supplementation improved hepatic division, but did not reduce the onset of liver failure [78,79]. In addition, intraperitoneal injection of leptin in wild type mice with no obesity increased mitotic counts during liver regeneration [78]. Collectively, these results suggest that adipokines play a significant role in hepatocellular proliferation. ...
Cell division is essential for organismal growth and tissue homeostasis. It is exceptionally significant in tissues chronically exposed to intrinsic and external damage, like the liver. After decades of studying the regulation of cell cycle by extracellular signals, there are still gaps in our knowledge on how these two interact with metabolic pathways in vivo. Studying the cross-talk of these pathways has direct clinical implications as defects in cell division, signaling pathways, and metabolic homeostasis are frequently observed in liver diseases. In this review, we will focus on recent reports which describe various functions of cell cycle regulators in hepatic homeostasis. We will describe the interplay between the cell cycle and metabolism during liver regeneration after acute and chronic damage. We will focus our attention on non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis. The global incidence of non-alcoholic fatty liver disease is increasing exponentially. Therefore, understanding the interplay between cell cycle regulators and metabolism may lead to the discovery of novel therapeutic targets amenable to intervention.
... The context of injury could also be important when determining when endocrine factors could be employed. For example, liver regenerative ability is reduced in leptin-deficient mice (ob 2 /ob 2 ), suggesting that leptin signaling promotes competence for regeneration (160,161). When these mice are treated with leptin after partial hepatectomy, there is no effect; however, leptin treatment restores regenerative ability after toxic injury when wound-healing actions of leptin might come into play (160,161). ...
... For example, liver regenerative ability is reduced in leptin-deficient mice (ob 2 /ob 2 ), suggesting that leptin signaling promotes competence for regeneration (160,161). When these mice are treated with leptin after partial hepatectomy, there is no effect; however, leptin treatment restores regenerative ability after toxic injury when wound-healing actions of leptin might come into play (160,161). Similarly, differences in the type of injury or amputation could result in different factors involved in regenerative ability. ...
Studies aiming to uncover primary mechanisms of regeneration have predominantly focused on genetic pathways regulating specific stages in the regeneration process: wound healing, blastema formation, and pattern formation. However, studies across organisms show that environmental conditions and the physiological state of the animal can affect the rate or quality of regeneration, and endocrine signals are likely the mediators of these effects. Endocrine signals acting directly on receptors expressed in the tissue or via neuroendocrine pathways can affect regeneration by regulating immune response to injury, allocation of energetic resources, or by enhancing or inhibiting proliferation and differentiation pathways involved in regeneration. This review discusses the cumulative knowledge in the literature about endocrine regulation of regeneration and its importance in future research to advance biomedical research.
... Next, we focused on insulin-stimulated DNA synthesis in H4IIEC3 cells because this is crucial for the proliferation of hepatic cells [21]. Insulin resistance has also been shown to induce an inhibitory effect on DNA synthesis [22,23]. At first, we tested the effect of SAR405 on DNA synthesis by H4IIEC3 cells. ...
... Insulin resistance has been shown to induce an inhibitory effect on DNA synthesis [22,23]. Since Db model cells reproduce aberrant pathological processes at the cellular level, we believe that these diseased cells are a useful tool to examine the molecular mechanisms of diabetic processes, which had only been previously observed in pathological tissues or patients. ...
Phosphatidylinositol-3-phosphate (PI3P) is a lipid that accumulates in the early endosomal membrane, and acts as a scaffold to recruit proteins that contain a PI3P-binding domain, such as the FYVE domain. In this study, we examined the effect of PI3P depletion on the insulin response in rat hepatoma-derived H4IIEC3 cells. We found that insulin treatment induced the transient formation of an actin domain structure, a mesh-like tangled network of actin filaments where phosphorylated Akt, endosomal proteins, and PI3P accumulated. Actin domain formation was repressed by the depletion of PI3P by SAR405, an inhibitor of the class III PI3 kinase, Vps34, by the inhibition of PI3P function by the competitive binding of an excess amount of GST-fused 2xFYVE protein to intracellular PI3P, and by the use of diabetic model cells, in which PI3P was depleted. SAR405 did not affect the phosphorylation level of Akt, and the transcriptional regulation of gluconeogenic and cholesterol synthetic genes after insulin treatment. Interestingly, insulin-induced DNA synthesis was specifically inhibited by SAR405, cytochalasin B, and also in diabetic model cells. These results suggest that PI3P is required for the formation of actin domains, which affected a signaling pathway downstream of Akt associated with DNA synthesis in H4IIEC3 cells.
... On the contrary, there is considerable evidence that fatty livers are suboptimal for surgical resection or transplantation, predominantly because of their increased susceptibility to ischemia-reperfusion injury and their disrupted regenerative response [23][24][25] . However, depending on the experimental model used, discrepant data regarding the regenerative capacity of steatotic livers exist [26][27][28][29][30] . ...
Abstract Transient hepatic steatosis upon liver resection supposes functional relationships between lipid metabolism and liver regeneration. Repin1 has been suggested as candidate gene for obesity and dyslipidemia by regulating key genes of lipid metabolism and lipid storage. Herein, we characterized the regenerative potential of mice with a hepatic deletion of Repin1 (LRep1−/−) after partial hepatectomy (PH) in order to determine the functional significance of Repin1 in liver regeneration. Lipid dynamics and the regenerative response were analyzed at various time points after PH. Hepatic Repin1 deficiency causes a significantly decreased transient hepatic lipid accumulation. Defects in lipid uptake, as analyzed by decreased expression of the fatty acid transporter Cd36 and Fatp5, may contribute to attenuated and shifted lipid accumulation, accompanied by altered extent and chronological sequence of liver cell proliferation in LRep1−/− mice. In vitro steatosis experiments with primary hepatocytes also revealed attenuated lipid accumulation and occurrence of smaller lipid droplets in Repin1-deficient cells, while no direct effect on proliferation in HepG2 cells was observed. Based on these results, we propose that hepatocellular Repin1 might be of functional significance for early accumulation of lipids in hepatocytes after PH, facilitating efficient progression of liver regeneration.
... It has been proposed that NASH livers are more vulnerable to surgical interventions because of decreased liver regeneration capacity (LRC) [7] . Previously, LRC has been studied in various rodent models of NAFLD/NASH generally based on the use of the methionine-choline deficiency diet (MCD) [7][8][9][10][11][12] , choline deficiency diet (CDD) [13][14][15][16] , simple high-fat diets (HFD) [17,18] and the genetic leptin-deficiency model [19][20][21][22][23][24][25] . These are widely accepted models of NAFLD/NASH, yet the animals lack many of the clinical and/or histopathological features related to human NAFLD/NASH. ...
AIM
To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH).
METHODS
Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration.
RESULTS
The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05).
CONCLUSION
NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
... Increasing evidence indicates that NAFLD strongly afects the intrinsic proliferative properties of hepatocytes. Many signs of impaired proliferation have been found in fatty hepatocytes (41)(42)(43). ...
La Liver Kinase B1 (LKB1) est une protéine pléiotrope, impliquée dans divers processus biologiques. Dans le foie, LKB1 est notamment connue pour être un régulateur clé du métabolisme et de la polarité cellulaire. Au cours de notre étude, nous avons investigué l’implication de LKB1 dans le contrôle de la prolifération des hépatocytes au cours du processus de régénération hépatique physiologique (hépatectomie partielle des 2/3). Nous avons démontré que la perte de Lkb1, spécifiquement dans les hépatocytes, favorise la récupération de la masse hépatique après hépatectomie partielle, en induisant une augmentation drastique de la réponse proliférative hépatocytaire, indépendamment de la balance métabolique/énergétique. Ainsi, LKB1 agit comme un senseur négatif de la prolifération et régule la transition G0/G1, en particulier en contrôlant la signalisation de l’EGFR (Epidermal Growth Factor Receptor). Par ailleurs, plus tard pendant la régénération, LKB1 garantit également l’intégrité mitotique. En effet, la suppression de Lkb1 entraîne des altérations majeures de la formation du fuseau mitotique. Nos résultats établissent également que LKB1 contrôle la polarité de la division cellulaire, indépendamment de l'activité de l’AMPK (AMP-activated protein kinase), une cible clé de LKB1. Par conséquent, la perte de LKB1 conduit à une altération majeure du profil de ploïdie, au stade tardif du processus de régénération. L’ensemble de notre étude souligne le double rôle de LKB1, au cours de la régénération hépatique, en tant que gardien de la prolifération hépatocytaire et de l'intégrité génomique.
... Thus, IDO1 induces immune tolerance via several mechanisms, and its role has been examined under several pathological conditions including cancer, infectious diseases, and auto immune diseases. The 70% PHx model has been widely used to examine the mechanisms of liver regeneration in many studies [14][15][16], but the role of IDO1 remains unclear in liver regeneration. Although several reagents can help the liver regeneration in basic studies, these reagents are hardly used at clinical sites. ...
Background and aim:
The inflammatory response accelerates early liver regeneration after liver injury and resection. Recent studies have demonstrated that indoleamine 2,3-dioxygenase-1 (IDO1) suppresses the activation of inflammatory cells and induces immune tolerance. In this study, we examined the role of IDO1 in liver regeneration after partial hepatectomy (PHx).
Methods:
WT or IDO1-knockout (IDO1-KO) mice received 70% PHx. The liver-body weight ratio after PHx was measured and hepatocyte growth was assessed by immunostaining. The expression of cell cycle genes and pro-inflammatory cytokines in the liver was analyzed by quantitative RT-PCR. In addition, 1-methyl-DL-tryptophan (1-MT), which is an IDO1 inhibitory agent, was given to WT mice and the liver-body weight ratio was measured after PHx.
Results:
The liver-body weight ratio was significantly increased in IDO1-KO mice compared with that in WT mice after PHx. More Ki-67-positive cells were present in IDO1-KO mice than in WT mice after PHx. The expression of cell cycle genes (cyclin D1, cyclin E) and pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) was up-regulated in the remnant liver of IDO1-KO mice compared with WT mice. Moreover, treatment with 1-MT promoted liver regeneration.
Conclusion:
IDO1 deficiency promoted early liver regeneration after PHx, indicating that IDO1 suppresses the production of inflammatory cytokines and subsequently inhibits hepatocyte proliferation during liver regeneration.
