Role In Life Research Articles

Fsp27/CIDEC is a CREB target gene induced during early fasting in liver and regulated by FA oxidation rate

FSP27 [cell death-inducing DFFA-like effector c (CIDEC) in humans] is a protein associated with lipid droplets that downregulates the fatty acid oxidation (FAO) rate when it is overexpressed. However, little is known about its physiological role in liver. Here, we show that fasting regulates liver expression of Fsp27 in a time-dependent manner. Thus, during the initial stages of fasting, a maximal induction of 800-fold was achieved, whereas during the later phase of fasting, Fsp27 expression decreased. The early response to fasting can be explained by a canonical PKA-CREB-CRTC2 signaling pathway because: i) CIDEC expression was induced by forskolin, ii) Fsp27 promoter activity was increased by CREB, and iii) Fsp27 expression was upregulated in the liver of Sirt1 knockout animals. Interestingly, pharmacological (etomoxir) or genetic (Hmgcs2 interference) inhibition of the FAO rate increases the in vivo expression of Fsp27 during fasting. Similarly, CIDEC expression was upregulated in HepG2 cells by either etomoxir or HMGCS2 interference. Our data indicate that there is a kinetic mechanism of autoregulation between short- and long-term fasting, by which free FAs delivered to the liver during early fasting are accumulated/exported by FSP27/CIDEC, whereas over longer periods of fasting, they are degraded in the mitochondria through the carnitine palmitoyl transferase system.

Response to Comment on: Visinoni et al. The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity. Diabetes 2012;61:1122–1132

We thank Masotti (1) for his interest and comment in this issue of Diabetes on our recently published article (2). In his letter, Masotti proposed, on the basis of our study findings and those from his own laboratory, that the glycolytic/gluconeogenic pathways may play an integral role in body weight regulation. Fructose-1,6-bisphosphate is not only the key substrate in gluconeogenesis for fructose-6-phosphate production but is also the substrate for the production of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate via the enzyme aldolase A ( ALDOA )—a glycolytic-pathway activated reaction. Masotti and colleagues (3) recently demonstrated that increased expression of microRNA-122 was associated with the development of nonalcoholic fatty liver disease in rats fed a …

Comment on: Visinoni et al. The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity. Diabetes 2012;61:1122–1132

In the May 2012 issue of Diabetes , Visinoni et al. (1) described the role of liver fructose-1,6-bisphosphatase (FBP-1) in regulating appetite and adiposity and in contributing to body weight regulation. In transgenic mice overexpressing FBP-1 , they observed a lean body weight phenotype and ∼50% reduction of adiposity that was supported by a reduction of food intake. In keeping with this evidence, appetite-stimulating neuropeptide Y and Agouti-related peptide were found to be significantly suppressed. The authors observed an inversion of the lean body weight phenotype by pharmacologic inhibition of FBP-1, suggesting a crucial role for this enzyme in the presence of excess nutrients/fats. FBP-1 is an enzyme in …

The role of Smad ubiquitination regulatory factor 1 in hepatocellular carcinoma

To determine the expression level of Smad ubiquitination regulatory factor 1 (SMURF1) gene in hepatocellular carcinoma, and to explore its role in liver cancer. With non-neoplastic adjacent normal tissues as controls, real-time PCR and Western blotting were used for measuring the expression of SMURF1 mRNA and protein in 89 samples of hepatocellular carcinoma. Correlations between SMURF1 expression and clinical features were explored. Following transfection of SMURF1--specific small interference RNA(siRNA), the apoptosis and proliferation of hepatic cancer cells Hep G2 were detected using flow cytometry and MTT assays . The expression of SMURF1 mRNA and protein were significantly higher in hepatocellular cancer tissues compared with the paired normal tissues (P< 0.05). The expression of SMURF1 however did not correlate with any clinical features (P> 0.05). Transfection of SMURF1-specific siRNA can promote the apoptosis whilst inhibit the proliferation of Hep G2 cells. The expression of SMURF1 is enhanced in hepatocellular carcinoma, which may have played a role in the disease through affecting apoptosis and proliferation of hepatic cancer cells.

Notch Signaling Is Activated in Human Hepatocellular Carcinoma and Induces Tumor Formation in Mice

The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer. The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and α-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method. AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 reduced their proliferation in vitro. Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro.

RNA interference targeting RelB attenuates liver ischemia/reperfusion injury

BackgroundRNA interference targeting RelB can significantly attenuate ischemia/reperfusion (I/R)-induced renal dysfunction, but its roles in liver I/R injury remain to be defined. We have investigated whether siRNA targeting of RelB in liver could also elicit protection against I/R injury. Materials and methodsA RelB miRNA RNAi expression plasmid, a scrambled plasmid, or phosphate-buffered saline (50 μg of the plasmid diluted in phosphate-buffered saline, 8% wt/vol) were rapidly injected, within 6–8 s, into mouse tail veins 24 h before liver I/R. Mice were subjected to 30 min of 70% hepatic ischemia or to a sham operation. Six h after reperfusion, blood and liver tissue samples were collected for subsequent assays. ResultsThe expression level of RelB was reduced in the RelB RNAi group compared with the control group, while it was increased in the I/R group. In the sham group, malondialdehyde, myeloperoxidase (MPO), and superoxide dismutase serum levels were almost the same, but the alanine aminotransferase level in the untreated group was 20- to 25-fold lower than in the other groups. In I/R-treated mice, although alanine aminotransferase, malondialdehyde, and MPO serum levels in the RelB RNAi group were lower than in other groups, all were higher than in the sham group. Silencing RelB could inhibit the decrease of superoxide dismutase activity and the upregulation of MPO and tumor necrosis factor α induced by I/R injury. ConclusionsSilencing RelB can protect the liver against I/R-induced damage. Therefore, it is a promising therapeutic target for protection against I/R injury in the liver.

Role of liver X receptors α and β in psoriasis

Role of liver X receptors α and β in psoriasis

Drosophila melanogaster Acetyl-CoA-Carboxylase Sustains a Fatty Acid–Dependent Remote Signal to Waterproof the Respiratory System

Fatty acid (FA) metabolism plays a central role in body homeostasis and related diseases. Thus, FA metabolic enzymes are attractive targets for drug therapy. Mouse studies on Acetyl-coenzymeA-carboxylase (ACC), the rate-limiting enzyme for FA synthesis, have highlighted its homeostatic role in liver and adipose tissue. We took advantage of the powerful genetics of Drosophila melanogaster to investigate the role of the unique Drosophila ACC homologue in the fat body and the oenocytes. The fat body accomplishes hepatic and storage functions, whereas the oenocytes are proposed to produce the cuticular lipids and to contribute to the hepatic function. RNA–interfering disruption of ACC in the fat body does not affect viability but does result in a dramatic reduction in triglyceride storage and a concurrent increase in glycogen accumulation. These metabolic perturbations further highlight the role of triglyceride and glycogen storage in controlling circulatory sugar levels, thereby validating Drosophila as a relevant model to explore the tissue-specific function of FA metabolic enzymes. In contrast, ACC disruption in the oenocytes through RNA–interference or tissue-targeted mutation induces lethality, as does oenocyte ablation. Surprisingly, this lethality is associated with a failure in the watertightness of the spiracles—the organs controlling the entry of air into the trachea. At the cellular level, we have observed that, in defective spiracles, lipids fail to transfer from the spiracular gland to the point of air entry. This phenotype is caused by disrupted synthesis of a putative very-long-chain-FA (VLCFA) within the oenocytes, which ultimately results in a lethal anoxic issue. Preventing liquid entry into respiratory systems is a universal issue for air-breathing animals. Here, we have shown that, in Drosophila, this process is controlled by a putative VLCFA produced within the oenocytes.

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases.

Lipid Metabolism and Neuroinflammation in Alzheimer's Disease: A Role for Liver X Receptors

Liver X receptors (LXR) are nuclear receptors that have emerged as key regulators of lipid metabolism. In addition to their functions as cholesterol sensors, LXR have also been found to regulate inflammatory responses in macrophages. Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive decline associated with inflammation. Evidence indicates that the initiation and progression of AD is linked to aberrant cholesterol metabolism and inflammation. Activation of LXR can regulate neuroinflammation and decrease amyloid-β peptide accumulation. Here, we highlight the role of LXR in orchestrating lipid homeostasis and neuroinflammation in the brain. In addition, diabetes mellitus is also briefly discussed as a significant risk factor for AD because of the appearing beneficial effects of LXR on glucose homeostasis. The ability of LXR to attenuate AD pathology makes them potential therapeutic targets for this neurodegenerative disease.

Cyanidin-3-O-β-glucoside induces oxysterol efflux from endothelial cells: Role of liver X receptor alpha

ObjectivesOxidized sterols are toxic to endothelial cells and play a central role in promoting atherogenesis. In this study, we evaluated the impact of anthocyanin, a class of flavonoid compounds, on oxysterol efflux from endothelial cells and the underlying mechanism. Methods and resultsThe human aortic ECs (HAECs) were incubated with anthocyanin cyanidin-3-O-β-glucoside (C3G) for different times. C3G treatment upregulates ABCG1 and ABCA1 expression in a dose-dependent manner in HAECs. Moreover, C3G promotes the efflux of cholesterol mainly 7-ketocholesterol (7-KC) from HAECs in an ABCG1-dependent manner. As a result, C3G abrogated the 7-KC-mediated increase of reactive oxygen species (ROS) and apoptosis in HAECs. Furthermore, C3G treatment reverses the inhibition of endothelial nitric oxide synthase (eNOS) activity by 7-KC, leading to the preservation of nitric oxide (NO) bioavailability. The induction of ABCG1 and its mediated 7-KC efflux from HAECs by C3G resulted from liver X receptor α (LXRα) activation, which was confirmed by its blockage of ABCG1 expression after pharmacological or small interfering RNA inhibition of LXRα. ConclusionsThese data uncover a novel mechanism by which C3G ameliorates oxysterol-induced oxidative damage on endothelial cells.

Tissue-specific mRNA expression patterns reveal a coordinated metabolic response associated with genetic selection for milk production in cows

The molecular mechanisms regulating the physiological adaptation of tissues important for nutrient partitioning and metabolism in lactating cows are still not completely understood. The aim of our study was to identify tissue-specific regulatory mechanisms necessary to accommodate metabolic changes associated with different genetic potential for milk performance. For this purpose, we analyzed mRNA expression of genes involved in energy metabolism of segregating F(2) beef type cows with a combined genetic dairy and beef background (Charolais × German Holstein cross, CH×GH) in contrast to purebred German Holstein (GH) dairy cows. Three groups of cows differing in milk performance were examined using quantitative real-time PCR in liver, mammary gland, and skeletal muscle. Our results describe substantial tissue-specific differences in mRNA transcription profiles between cow groups in relation to their genetic potential for milk performance and highlight genes exhibiting specific, partially yet-unknown functions in dairy and beef type cows, e.g., upregulation of PCK2 transcripts in the mammary gland and FBP2 transcripts in skeletal muscle of dairy cows. Noticeably, PCCA and PPARGC1A mRNA abundance varied significantly across experimental groups in all three tissues, pointing to potential key gene functions in the metabolic adaptation relative to divergent milk production performance. Correlations of mRNA expression levels to milk performance traits indicate that gene transcriptional processes may play a regulatory role in liver, mammary gland, and skeletal muscle to enable cows with different genetic potential for milk performance to cope with metabolic lactation-associated challenges.

Abstract 313: The Nuclear Liver X Receptor as a Potential Regulator of Interleukin 18 Binding Protein in the Lung

Background and Objectives: Second hand smoke (SHS) is a major risk factor for development of chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis in non-smokers. The role of liver X receptor (LXR) in the pathogenesis of COPD/emphysema is not well understood. Both LXR and LXR were found in the lung. The alpha isoform is involved in the regulation of lipid metabolism whereas the beta isoform is involved in the regulation of inflammation. Here we investigate the effects of cigarette smoke (CS) on LXR activation as well as target gene and protein regulation in vivo and in vitro . Methods: Sprague Dawley rats were exposed to SHS for 2 months. Lung tissue and bronchoalveolar lavage fluid (BALf) cells were examined for LXR gene expression and emphysema development (measured by mean linear intercept). Rat alveolar macrophages (AM) and rat pulmonary microvascular endothelial cells (RPMVEC) were treated with cigarette smoke extract (CSE), LPS or DMHCA, a steroidal LXR agonist) in vitro and changes in LXR and its target gene and protein expression were examined. Results: LXR gene expression was impaired and the expression of the LXR target gene, ATP binding cassette transporter A1 (ABCA1), was significantly downregulated in BALf cells from SHS-exposed rat lungs and in rat AM treated with CSE. Real-time PCR revealed significant downregulation of LXR and upregulation of LXR in BALf cells after 1 month of SHS exposure. Similar changes were also observed in CSE-treated RPMVEC. There was a significant increase in the pro-inflammatory interleukin 18 (IL18) levels in BALf cells of SHS-exposed rats, whereas the levels of IL18 binding protein (IL18bp), an endogenous inhibitor of IL18, remained unchanged. Interestingly, activation of LXR led to upregulation of IL18bp in AM and peritoneal macrophages where potential LXR response element (LXRE) sites were indentified, in silico , in the promoter region of IL18bp. Additionally, emphysematous changes and foamy macrophage accumulation were observed in lungs of LXR-deficient mice. Conclusions: These findings implicate IL18bp as a new LXR target gene involved in the anti-inflammatory signaling pathway. Our data suggest that LXR agonist treatment may be beneficial in the prevention and treatment of CS-induced emphysema.

All-trans retinoic acid preconditioning protects against liver ischemia/reperfusion injury by inhibiting the nuclear factor kappa B signaling pathway

BackgroundInflammatory response plays a pathogenic role in liver ischemia/reperfusion (I/R) injury. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A with anti-inflammatory effects. However, there are few reports on the anti-inflammatory effects of ATRA on liver I/R injury. The purpose of this study was to investigate the effects of ATRA on liver I/R injury and related mechanisms. MethodsA total of 54 male Sprague–Dawley rats were randomly divided into three groups (18 rats each), namely, sham, I/R, and I/R+ATRA groups. ATRA was intraperitoneally administered at a dose of 15mg/kg/d 14d before ischemia surgery. The segmental (70%) hepatic ischemia model was used by clamping the portal vein, hepatic artery, and bile duct of the left and median for 1h. The rats were sacrificed 3, 6, and 24h after reperfusion, and blood and liver tissue samples were obtained. Liver injury was evaluated by biochemical and histopathologic examinations. Myeloperoxidase activity was spectrophotometrically measured. The expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6 was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Liver nuclear factor kappa B (NF-κB) was detected by immunohistochemistry. The expression of NF-κB p65 and inhibitor NF-κB-α (IκBα) was determined by Western blot analysis. ResultsThe serum alanine aminotransferase level, Suzuki scores of hepatic histology, and hepatic myeloperoxidase activity, as indices of hepatic injury, were increased after reperfusion. The increase was attenuated by preadministration with ATRA. Compared with the I/R group, ATRA treatment increased IκBα expression and suppressed NF-κB p65 expression. Subsequently, the levels of tumor necrosis factor-α and interleukin-6 after liver I/R were effectively downregulated. ConclusionsATRA administration can significantly attenuate I/R injury in rat liver. The protective mechanism is related to its anti-inflammatory function of inhibiting NF-κB activation.

The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-β-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation.

The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells

The NR4A orphan nuclear receptors Nur77, Nurr1, and Nor1 exert multiple cellular and metabolic functions. These transcriptional regulators are activated in response to extracellular stresses, including lipotoxic fatty acids (FA) and proinflammatory cytokines. The contribution of NR4As to β-cell pathophysiology is, however, unknown. We have therefore examined the role of NR4As as downstream contributors to FA-induced β-cell dysfunctions. Human pancreatic islets and insulinoma β-cells were used to determine transcriptional programs elicited by NR4A, which were compared to those triggered by palmitate treatment. Functional studies evaluated the consequence of an increased NR4A expression on insulin biosynthesis and secretion and cell viability in insulinoma β-cells. FA and cytokine treatment increased NR4A expression in pancreatic β-cells, with Nur77 being most highly inducible in murine β-cells. Nur77, Nurr1, or Nor1 modulated common and distinct clusters of genes involved notably in cation homeostasis and insulin gene transcription. By altering zinc homeostasis, insulin gene transcription, and secretion, Nur77 was found to be a major transcriptional mediator of part of FA-induced β-cell dysfunctions. The repressive role of Nur77 in insulin gene regulation was tracked down to protein-protein interaction with FoxO1, a pivotal integrator of the insulin gene regulatory network. The present study identifies a member of the NR4A nuclear receptor subclass, Nur77/NR4A1, as a modulator of pancreatic β-cell biology. Together with its previously documented role in liver and muscle, its role in β-cells establishes Nur77 as an important integrator of glucose metabolism.

Role of liver X receptors in cholesterol efflux and inflammatory signaling (Review)

Liver X receptors (LXRs) are nuclear receptors that play a central role in cholesterol metabolism. When activated, LXRs induce a series of genes that are involved in cholesterol efflux, absorption, transport and excretion. In recent studies, LXRs have also been shown to play an important role in inflammatory signaling. LXR agonists show promise as potential therapeutics, given their anti-atherogenic and anti-inflammatory properties. The function of LXRs in cholesterol efflux and inflammatory signaling make them attractive as therapies for cardiovascular and inflammatory diseases.

5．メタボリックシンドロームにおける肝臓の役割：内分泌学からのアプローチ

5．メタボリックシンドロームにおける肝臓の役割：内分泌学からのアプローチ

Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation

The hypothesis tested in this study was that cholesterol esterification by ACAT2 would increase cholesterol absorption efficiency by providing cholesteryl ester (CE) for incorporation into chylomicrons. The assumption was that absorption would be proportional to Acat2 gene dosage. Male ACAT2⁺/⁺, ACAT2⁺/⁻, and ACAT2⁻/⁻ mice were fed a diet containing 20% of energy as palm oil with 0.2% (w/w) cholesterol. Cholesterol absorption efficiency was measured by fecal dual-isotope and thoracic lymph duct cannulation (TLDC) methods using [³H]sitosterol and [¹⁴C]cholesterol tracers. Excellent agreement among individual mice was found for cholesterol absorption measured by both techniques. Cholesterol absorption efficiency in ACAT2⁻/⁻ mice was 16% compared with 46-47% in ACAT2⁺/⁺ and ACAT2⁺/⁻ mice. Chylomicrons from ACAT2⁺/⁺ and ACAT2⁺/⁻ mice carried ∼80% of total sterol mass as CE, whereas ACAT2⁻/⁻ chylomicrons carried >90% of sterol mass in the unesterified form. The total percentage of chylomicron mass as CE was reduced from 12% in the presence of ACAT2 to ∼1% in ACAT2⁻/⁻ mice. Altogether, the data demonstrate that ACAT2 increases cholesterol absorption efficiency by providing CE for chylomicron transport, but one copy of the Acat2 gene, providing ∼50% of ACAT2 mRNA and enzyme activity, was as effective as two copies in promoting cholesterol absorption.

Ultrastructure of liver progenitor/oval cells in children with nonalcoholic steatohepatitis

Very interesting reports have appeared lately on the role of liver progenitor/oval cells in the morphogenesis and development of nonalcoholic steatohepatits (NASH) in adult patients and experimental animals. However, no literature data concerning pediatric patients have been available. Therefore, the purpose of the study was to evaluate the ultrastructure of the population of liver progenitor/oval cells in the biopsy material from children with previously clinocopathologically diagnosed NASH. Electron-microscopic examinations were conducted on fresh tissue samples collected from 10 children with NASH (aged 2-14 years), which were fixed with a solution of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M cacodylate buffer. Ultrastructural examinations of the liver progenitor/oval cells in children with NASH show a quite prominent number of these cells, especially their two types, hepatic progenitor cells (HPCs) and intermediate hepatocyte-like cells (IHCs), with intermediate bile-like cells being the least frequent. They were found to occur single or in clusters of two, seldom of three, and frequently in the areas of advanced liver fibrosis or close to them. Many times, these cells were accompanied by hepatocytes showing a varying degree of death, to total cell disintegration. Interesting was the presence of activated nonparenchymal liver cells, i.e. Kupffer cells/macrophages and hepatic stellate cells, frequently found to adhere to the hepatic oval cells. The current study suggests a marked involvement of the population of liver progenitor/oval cells, mainly HPCs and IHCs, in the development of nonalcoholic steatohepatitis in pediatric patients, especially in fibrosis progression.