Enlargement Of Hepatocytes Research Articles

Accumulation of polyunsaturated lipids fuels ferroptosis to promote liver failure after extended hepatectomy in mice

Background Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive. Methods PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated. Results PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice. Conclusions Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.

Short-chain chlorinated paraffins induce liver injury in mice through mitochondrial disorders and disruption of cholesterol-bile acid pathway

Short-chain chlorinated paraffins (SCCPs) are pervasive organic pollutants recognized for their persistence and bio-toxicity. This study investigated the hepatotoxic mechanisms of SCCPs at environmentally relevant concentration (0.7 μg/kg). The results showed that SCCPs exposure in mice resulted in dysregulated blood and liver lipids, marked by elevated cholesterol levels. Additionally, liver function was compromised, as indicated by increased levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Histopathological examination of liver tissue post-SCCPs exposure revealed hepatocyte enlargement, vacuolar degeneration, and mild ballooning degeneration. Mechanistically, SCCPs induced mitochondrial abnormalities, evidenced by heightened Hoechst 33258 fluorescence, and augmented reactive oxygen species and malondialdehyde levels in liver tissue. This was accompanied by a reduction in total antioxidant capacity, culminating in elevated apoptosis markers, including cytochrome C and caspase-3. Moreover, SCCPs perturbed hepatocellular energy metabolism, characterized by increased glycolysis, lactic acid, and fatty acid oxidation, alongside a disruption in the tricarboxylic acid cycle and a decline in mitochondrial energy metabolic function. Furthermore, SCCPs exposure downregulated the expression of genes involved in bile acid synthesis (cyp27a1, fxr, and shp), thereby precipitating the cholesterol-bile acid metabolism disorders and cholesterol accumulation. Collectively, these findings underscore that SCCPs, even at environmentally relevant levels, can induce lipid dysregulation, mitochondrial disorders and cholesterol deposition in the hepatocytes, contributing to liver damage. The study's insights contribute to a comprehension of SCCPs-induced hepatotoxicity and may inform potential preventative and treatment targets for hepatic damage associated with SCCPs exposure.

Fenofibrate induces liver enlargement in aging mice via activating the PPARα-YAP signaling pathway

Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator-activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through activation of the yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice, and senescence-accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effects of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area were comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrate that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effects of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings offer a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for the role of PPARα in liver enlargement.

AHR regulates liver enlargement and regeneration through the YAP signaling pathway

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligands that participates in many important physiological processes. Although AHR activation is associated with hepatomegaly, the underlying mechanism remains unclear. This study evaluated the effects of AHR activation on liver enlargement and regeneration in various transgenic mice and animal models. Activation of AHR by the non-toxic ligand YH439 significantly induced liver/body weight ratio in wild-type mice (1.37-fold) and AHRfl/fl.ALB-CreERT2 mice (1.54-fold). However, these effects not present in AHRΔHep mice. Additionally, the activation of AHR promotes hepatocyte enlargement (1.43-fold or 1.41-fold) around the central vein (CV) and increases number of Ki67+ cells (42.5-fold or 48.8-fold) around the portal vein (PV) in wild-type mice and AHRfl/fl.ALB-CreERT2 mice. In the 70 % partial hepatectomy (PHx) model, YH439 significantly induced hepatocyte enlargement (1.40-fold) and increased number of Ki67+ cells (3.97-fold) in AHRfl/fl.ALB-CreERT2 mice. However, these effects were not observed in AHRΔHep mice. Co-immunoprecipitation results suggested a potential protein-protein interaction between AHR and Yes-associated protein (YAP). Disruption of the association between YAP and transcription enhancer domain family member (TEAD) significantly inhibited AHR-induced liver enlargement and regeneration. Furthermore, AHR failed to induce liver enlargement and regeneration in YAPΔHep mice. Blocking the YAP signaling pathway effectively eliminated AHR-induced liver enlargement and regeneration. This study revealed the molecular mechanism of AHR regulation of liver size and regeneration through the activation of AHR-TEAD signaling pathway, thereby offering novel insights into the physiological role of AHR. These findings provide a theoretical foundation for the prevention and treatment of disorders associated with liver regeneration.

Ginkgo Biloba Extract Can Antagonize Subchronic Arsenite Exposure-Induced Hepatocyte Senescence by Inhibiting Oxidative Damage and Inflammation in Rats.

A growing body of evidence suggests that long-term arsenic exposure can induce liver injury. Our previous studies have demonstrated that liver injury occurs in arsenic-poisoning patients and arsenic-exposed rats. However, therapeutic targets are still unclear, and there is a lack of effective drugs. This study aimed to investigate the effects of sodium arsenite (arsenite) exposure on hepatocyte senescence and the intervention effect of ginkgo biloba extract in rats. In this study, 24 male Sprague-Dawley rats (weighing 180-200g) were randomized into three groups. The control group received a normal diet, and the arsenic-exposed group was given 10mg/L arsenite for 3months by free drinking along with a normal diet. The ginkgo biloba extract treatment group was consecutively administered EGb761 (10mg/kg, by gavage) for 1month following 2months of arsenite exposure. Our results showed that exposure to 10mg/L arsenite induced narrowing of the hepatic sinus space, enlargement of hepatocytes, and increased multinucleated hepatocytes and inflammatory cell infiltration in rat liver tissue compared with the normal control group. Moreover, 10mg/L arsenite also caused abnormal expression of inflammation-related indices (IL1-β, IL-6, TNF-α), oxidative damage-related indices (SOD, MDA, GPx), and senescence-related proteins (p16, p-p53, E2F1). EGb761 could effectively reduce the pathological damage of liver tissue and antagonize the abnormal expression of liver tissue inflammation and oxidative damage-related indices as well as cellular senescence-related proteins caused by arsenite exposure. Notably, EGb761 reduced the accumulation of arsenic in rat liver tissues. These results suggested that EGb761 could effectively alleviate subchronic arsenic exposure-induced senescence of hepatocytes, which may be achieved partially through inhibiting inflammation and oxidative damage in rats. This study may provide a new therapeutic target for arsenic-induced liver injury.

Peroxisome proliferator-activated receptor α agonist induces mouse hepatomegaly through the spatial hepatocyte enlargement and proliferation.

Peroxisome proliferator-activated receptor alpha (PPARα) activation-induced hepatomegaly is accompanied by hepatocyte hypertrophy around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area. However, the molecular mechanisms underlying this spatial change of hepatocytes remains unclear. In this study, we examined the characteristics and possible reasons for the zonation distinction of hypertrophy and proliferation during PPARα activation-induced mouse liver enlargement. Mice were injected with corn oil or a typical mouse PPARα agonist WY-14643 (100 mg·kg-1·d-1, i.p.) for 1, 2, 3, 5 or 10 days. At each time point, the mice were sacrificed after the final dose, and liver tissues and serum were harvested for analysis. We showed that PPARα activation induced zonal changes in hepatocyte hypertrophy and proliferation in the mice. In order to determine the zonal expression of proteins related to hepatocyte hypertrophy and proliferation in PPARα-induced liver enlargement, we performed digitonin liver perfusion to separately destroy the hepatocytes around the CV or PV areas, and found that PPARα activation-induced increase magnitude of its downstream targets such as cytochrome P450 (CYP) 4 A and acyl-coenzyme A oxidase 1 (ACOX1) levels around the CV area were higher compared with those around the PV area. Upregulation of proliferation-related proteins such as cell nuclear antigen (PCNA) and cyclin A1 (CCNA1) after WY-14643-induced PPARα activation mainly occurred around the PV area. This study reveals that the zonal expression of PPARα targets and proliferation-related proteins is responsible for the spatial change of hepatocyte hypertrophy and proliferation after PPARα activation. These findings provide a new insight into the understanding of PPARα activation-induced liver enlargement and regeneration.

Liver impact of growth hormone (GH) intermittent treatment during the growth period in mice.

Liver impact of prolonged GH-treatment given to non-GH-deficient growing mice between the third and eighth week of life was evaluated in both sexes. Tissues were collected 6h after last dose or four weeks later. Somatometric, biochemical, histological, immunohistochemical, RT-qPCR and immunoblotting determinations were performed. Five-week GH intermittent administration induced body weight gain and body and bone length increase, augmented organ weight, higher hepatocellular size and proliferation, and increased liver IGF1 gene expression. Phosphorylation of signaling mediators and expression of GH-induced proliferation-related genes was decreased in GH-treated mice liver 6h after last injection, reflecting active sensitization/desensitization cycles. In females, GH elicited EGFR expression, associated to higher EGF-induced STAT3/5 phosphorylation. Four weeks after treatment, increased organ weight concomitant to body weight gain was still observed, whereas hepatocyte enlargement reverted. However, basal signaling for critical mediators was lower in GH-treated animals and in male controls compared to female ones, suggesting signaling declination.

Impacts of ZnO and multi-walled carbon nanotubes (MWCNTs) on biological parameters of the Oriental river prawn Macrobrachium nipponense De Haan, 1849 (Decapoda: Caridea: Palaemonidae)

Abstract Nanomaterials (NMs) mainly settle on bottom sediments and accumulate in the benthos of aquatic communities. Decapod crustaceans, being deposit-omnivorous feeders, are appropriate biological models to assay the biological effects of NMs. The present study evaluated the effects of ZnO and multi-walled carbon nanotubes (MWCNTs) NMs separately and in combination on the activities of antioxidant enzymes on crustacean hyperglycemic hormone (CHH), hematology, reproductive performance, and hepatopancreas lesions the Oriental river prawn, Macrobrachium nipponense De Haan, 1849 [De Haan, 1833–1850]. We essayed concentrations of ZnO (0, 1, 10, 30, 50 mg l–1) and MWCNTs (0, 5, 10, 15, 20 mg l–1) and two higher concentrations of the NMs were compared in combined treatments. Both NMs showed dose-dependent effects on reproductive parameters of M. nipponense, especially the fertilization rate of eggs. Inter-molt and inter-spawn periods were postponed and reproduction stopped in 50 ppm ZnO and 15 and 20 ppm MWCNTs treatments. Our findings showed that the release of crustacean hyperglycemic hormone (CHH) and superoxide dismutase (SOD) enzyme activity are directly related to the NMs levels independently as well as in combination. NMs did not show any effect on the activities of alanine transaminase (ALT) and aspartate transaminase (AST) enzymes in muscle tissue independently, but the combined effects of the activities of these enzymes were significant. NMs caused hepatocyte enlargement, melanization, apoptosis, and necrosis damages in the hepatopancreas of prawns. The findings showed that ZnO and MWCNTs NMs have strong adverse biological effects on M. nipponense, and that this species is an appropriate bio-indicator and bio-monitor organism for NMs contaminations in the freshwater aquatic environments.

YAP regulates the liver size during the fasting-refeeding transition in mice.

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

High throughput proteomic analysis of Labeo rohita liver infected with Edwardsiella tarda

The liver is a multifunctional organ and very crucial for pathogenicity and toxicological analysis in fish. In this study, histopathological and proteomic analysis of liver tissue was performed to overview the changes in tissue anatomy and proteome profile following Edwardsiella tarda (Et) infection. The differential proteomic response against Et infection was investigated using label free quantitative proteomics. Compared to the control tissue, the histopathological changes in bacterial challenged group (ET) include hepatocyte enlargement and melanomacrophage centre (MMC) aggregation in response to disease. With the proteomic analysis, a total of 1275 proteins were identified of which 257 were found to be differentially expressed proteins (DEP) between the control and ET group. Functional analysis of DEPs using STRING and metascape tools revealed expression of proteins belonging to different pathways like ribosome, protein processing in the endoplasmic reticulum (rpl5a), metabolic pathways (acss2, prodha, cyp51a), oxidative phosphorylation (uqcrfs1, ndufb10, atp6v0d1), proteasome (psmd3), and N-glycan biosynthesis (dpm1) pathways. Proteins involved in response to the Et infection activate downstream processes of apoptosis, inflammatory cytokines (TIR, chp1, apoa1), MAC (c9, c5, c8a), PPAR signalling (acsl4), APR (a2m1, cp), and T-cell activation (Ilf2). A targeted proteomics approach (MRM) was used in rohu livers to validate differentially expressed proteins (itln2, steap4, gst, psap) involved in Et pathogenesis. Our results showed the putative histopathological effects of Et infection on liver tissue and insights into the metabolic and immune pathway-associated proteins that play a role during Et infection, thereby highlighting a potential way of enhancing fish immunity against bacteria. Our comprehensive liver proteome findings would contribute to understanding pathogenesis and revealing novel disease markers for rohu liver in Et infection.

HEPATOTOXICOPATHOLOGY EVALUATION OF DIMETHYLFORMAMIDE (DMF) ON MALE ALBINO RATS LIVERS

This experiment was aimed to investigate the Toxicopathological effect of N, N-Dimethylformamide (DMF) (1/10LD50) on the adult male rats' liver. Sixteen adult male rats were used in this experiment. After acclimatization for two weeks, they were divided equally into two groups as follows: Group-C-control: Normal diet and water for 30 days (n=8 rats).Group-T1: DMF 645.5mg/kg. B.W as 1/10LD50 for30 days ( n=8rats ) , after thirty days collected blood for liver enzymes analysis then all animals killed at the end of the experiment and the liver samples saved at 10% formalin for histopathological preparation. The results showed that serum liver enzymes (ALP, ALT, and AST) concentrations of adult male rats after thirty days of oral DMF administration were significantly different (P<0.05) from the control group. Histopathological changes of group 1/10 LD50 (T1) group appear enlargement of hepatocytes with mild degeneration and mild hyperplasia of kupffer cells, and focal infiltration of inflammatory cells mainly lymphocytes in the portal area and a large area of necrosis.

Aronia melanocarpa Anthocyanin Extracts Improve Hepatic Structure and Function in High-Fat Diet-/Streptozotocin-Induced T2DM Mice.

Anthocyanins can prevent and ameliorate type 2 diabetes mellitus (T2DM), but its mechanism of action has not been fully established. IKK/NF-κB and JAK/Stat pathways have multiple effects, triggering T2DM. Liver abnormalities in individuals with T2DM are detrimental to glycemic control. We determined whether anthocyanins could improve the liver of individuals with T2DM using IKK/NF-κB and JAK/Stat. We established a T2DM mouse model using a high-fat diet and streptozotocin and then performed Aronia melanocarpa anthocyanin extracts' (AMAEs') administration for 5 weeks. AMAEs improved blood glucose and hyperinsulinemia of T2DM mice. In the liver of AMAE-administered T2DM mice, ROS, IKKβ/NF-κB p65, and JAK2/Stat3/5B signalings were down-regulated, thereby reducing the suppressor of cytokine signaling 3 (SOCS3), iNOS, and inflammatory mediators. AMAE-improved hyperinsulinemia also down-regulated SOCS3 by decreasing p-Stat5B in hepatocytes. AMAEs enhanced glucose uptake and conversion and decreased hepatocyte enlargement and inflammatory cells in the liver of T2DM mice. These indicated that AMAEs could alleviate oxidative stress, insulin resistance, inflammation, and tissue damage in the liver of T2DM mice through inhibiting NF-κB p65 and Stat3/5B.

The cooperative interplay among inflammation, necroptosis and YAP pathway contributes to the folate deficiency-induced liver cells enlargement.

Change in cell size may bring in profound impact to cell function and survival, hence the integrity of the organs consisting of those cells. Nevertheless, how cell size is regulated remains incompletely understood. We used the fluorescent zebrafish transgenic line Tg-GGH/LR that displays inducible folate deficiency (FD) and hepatomegaly upon FD induction as in vivo model. We found that FD caused hepatocytes enlargement and increased liver stiffness, which could not be prevented by nucleotides supplementations. Both in vitro and in vivo studies indicated that RIPK3/MLKL-dependent necroptotic pathway and Hippo signaling interactively participated in this FD-induced hepatocytic enlargement in a dual chronological and cooperative manner. FD also induced hepatic inflammation, which convenes a dialog of positive feedback loop between necroptotic and Hippo pathways. The increased MMP13 expression in response to FD elevated TNFα level and further aggravated the hepatocyte enlargement. Meanwhile, F-actin was circumferentially re-allocated at the edge under cell membrane in response to FD. Our results substantiate the interplay among intracellular folate status, pathways regulation, inflammatory responses, actin cytoskeleton and cell volume control, which can be best observed with in vivo platform. Our data also support the use of this Tg-GGH/LR transgenic line for the mechanistical and therapeutic research for the pathologic conditions related to cell size alteration.

Long-term treatment with the mPXR agonist PCN promotes hepatomegaly and lipid accumulation without hepatocyte proliferation in mice.

Pregnane X receptor (PXR) is highly expressed in the liver and plays a pivotal role in xenobiotic and endobiotic metabolism. We previously reported that PXR activation by its specific mouse agonist pregnenolone 16α-carbonitrile (PCN) significantly induces liver enlargement and lipid accumulation. However, the effect of long-term PCN treatment on PXR and mouse liver is still unknown. This study aimed to explore the influence of long-term administration of PCN on mouse liver and hepatic lipid homeostasis. Male C57BL/6 mice were injected intraperitoneally with PCN (100 mg/kgonce aweek) for 42 weeks. Serum and liver samples were collected for biochemical and histological analysis. PXR activation was investigated by Western blot. Ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS)-based lipidomics analysis was performed to explore the change in different lipid categories. The results showed that long-term treatment with PCN significantly promoted hepatomegaly without hepatocyte proliferation and enlargement. Long-term treatment with PCN did not upregulate PXR target proteins in mice, and there was no significant upregulation of CYP3A11, CYP2B10, UGT1A1, MRP2, or MRP4. Lipidomics analysis showed obvious hepatic lipid accumulation in the PCN-treated mice, and the most significant change was found in triglycerides (TGs). Additionally, long-term treatment with PCN had no risk for carcinogenesis. These findings demonstrated that long-term PCN treatment induces hepatomegaly and lipid accumulation without hepatocyte proliferation or enlargement.

Histopathological Changes in Liver and Heart Tissue Associated with Experimental Ultraviolet Radiation A and B Exposure on Wistar Albino Rats.

This study aims to evaluate the influences of ultraviolet radiation A and B (UVA + B) exposure on the liver and heart organs of albino rats. Female Wistar Albino rats, whose hair of the dorsal skin was shaved, were exposed to a combined UVA + B radiation for 2 h/day, for 4 weeks in order to be compared with the control group. Histopathological findings in vital organs (liver and heart) were evaluated. Tissues were fixed in 10% buffered formalin (pH = 7.2) and embedded in paraffin. The histopathological findings were examined on the H&E stained sections with light microscopy. The results show that the liver and the heart were injured in the UVA + B group. Liver tissue in the UVA + B group showed minimal vacuolation, enlargement of hepatocytes and bile duct proliferation, and the heart tissue showed hibernomas; uniform large cells resembling brown fat with coarsely granular to multivacuolated cytoplasm that is eosinophilic or pale with a small central nucleus. The number of hibernoma cases was significantly higher in the UVA + B group compared with the control group (P = 0.021). The control group showed normal liver and heart histology with normal adipose tissue in the pericardium. As a result, UVA + B exposure has toxic effects, especially on the liver and the heart of Wistar albino rats. UV radiation may cause such adverse effects in humans. Therefore, protection against the harmful effects of UV radiation is of significant importance for skin and organs.

Fenofibrate induced‐hepatomegaly and liver regeneration is PPARα dependent and partially related to the activation of YAP pathway

Background and ObjectiveFenofibrate, an agonist of peroxisome proliferator activated receptor α (PPARα), has been widely used as a lipid‐regulating agent in clinical practice. Recent studies found that fenofibrate can significantly induce hepatomegaly in mice, but the involved mechanisms remain unclear.MethodsThe effect of fenofibrate on hepatomegaly and liver regeneration was investigated in several strains of genetically‐modified mice including Pparafl/fland PparaΔHep mice. Staining assays were performed to investigate the effect of fenofibrate on hepatocyte size and proliferation during hepatomegaly and liver regeneration. AAV‐Yap shRNA mice model was further used to determine the role of YAP in PPARα‐induced hepatomegaly. Western blot analysis was used to detect the protein expressions of YAP signaling pathway as well as other factors potentially involved in fenofibrate‐induced hepatomegaly.ResultsThe study demonstrated that fenofibrate significantly induced liver enlargement in wild‐type and Pparafl/fl mice, while this effect was abolished in hepatocyte‐specific Ppara‐deficient (PparaΔHep) mice. Furthermore, fenofibrate significantly promoted liver regeneration in wild‐type mice following 70% partial hepatectomy (PHx). Staining assays revealed that fenofibrate promoted hepatocyte enlargement around the central vein area and hepatocyte proliferation around the portal vein area in wild‐type, Pparafl/fl and PHx mice. Fenofibrate regulated protein expressions of YAP and its downstream targets (CTGF, CRY61 and ANKRD1) as well as proliferation‐related proteins (CCNA1, CCND1 and CCNE1). Suppression of YAP using AAV‐Yap shRNA repressed fenofibrate‐induced hepatomegaly, as well as hepatocyte enlargement and proliferation. Other factors might also participate in fenofibrate‐induced hepatomegaly, including MYC, KRT23, RHOA and RAS.ConclusionThese studies revealed a novel role of fenofibrate in promoting liver enlargement and regeneration, which is PPARα dependent and partially related to the activation of YAP signaling pathway. These findings provide clinical relevance of fenofibrate as a potential medication for promoting liver regeneration.

Histopathological effects of titanium dioxide nanoparticles on the liver of Japanese quail Coturnix coturnix japonica

Titanium dioxide nanoparticles have multiple beneficial uses, as they are used in many medical, industrial, economic, and other fields. Despite these many benefits, it is not without harm to humans and animals if used without control. Therefore, the present study aimed to discover the histopathological effects of Titanium dioxide nanoparticles on the liver of Japanese quail, Coturnix coturnix japonica. The study included three groups, the first group, the control group, which were dosed with distilled water for four continuous days, and the second and third experimental groups, which were dosed with Titanium dioxide nanoparticles at a concentration of 20 and 40 mg/kg, respectively. Four, fourteen, thirty and sixty days after the experiment began, the birds were sacrificed. The results showed the emergence of many histological lesions in the liver of birds of the two experimental groups, to varying degrees, in the four periods, among the most prominent tissue lesions that appeared in the second experimental group, the emergence of necrosis, hemorrhage, vacuolation, congestion, ballooning swelling, in addition to infiltration of inflammatory cells. While in the third experimental group, histopathological lesions appeared similar to second group, in addition to sinuses dilatation, Kupffer cells hypertrophy, hepatocyte enlargement, and necrosis of the walls of blood vessels and bile ducts. The study concluded that direct exposure to Titanium dioxide nanoparticles leads to damage to the liver tissue of these birds, which may affect its function and thus endanger its life.

Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA

GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.

PHYTOPHARMACOLOGICAL EVALUATION OF HYDROALCOHOLIC EXTRACT OF BARK OF PONGAMIA GLABRA VENT. FOR ANTI-OBESITY ACTIVITY AND EFFECT ON LIPID PROFILE AND HEPATIC ENZYMES

Pongamia glabra is a native Indian subcontinent as well as south-east Asia drug used widely in many herbal formulations. The bark extract is used in the present study to evaluate its anti-obesity activity and its effect on lipid profile and hepatic enzyme. In-vivo studies were done using high fat diet along with DPMA model. Anti-obesity Evaluations included in the study was analysis of serum biochemical parameters (Serum Lipid Profile), determination of atherogenic index and coronary risk, Determination of Adiposity Levels, Fat Depot and Liver weight/Body weight Ratio (%) and histopathological analysis of liver tissues and adipose tissues. The results of the present study suggested that in actute toxicity studies, animals did not show any mortality at the dose of 500 mg/kg;bw. The Pongamia glabra bark at the dose of 500 mg/kg body weight found to show strong reducing effect on serum TC, TG and LDL levels among the treatments. The atherogenic index and coronary risk index showed significant reduction when treated with hydroalcoholic extract of Pongamia glabra bark extract. A significant increase in Lee index was observed in rat fed with high fat dies. The study showed that Weight of different body fat depots i.e. epitdidymal, retroperitoneal, mesenteric fat depot and total fat were significantly increased in HFD group as compared to the normal control group of rat. The histopathological studies suggested that Pongamia glabra bark extracts suppress the enlargement of hepatocytes and the accumulation of vesicles in the hepatic tissues. The present study thus clearly indicates that Pongamia glabra stem bark has a significant anti-obesity effect which supports its traditional uses.

YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice.

Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. This study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.