• Animals
• Pancreatitis-Associated Proteins/metabolism
• Humans
• Mice
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Glycosylation
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Mice, Transgenic
• Acetylglucosamine/metabolism
• N-Acetylglucosaminyltransferases/metabolism
• Male

• CMA
• LAMP2A
• Liver injury
• NLRP3 inflammasome
• Nrf2
• Severe acute pancreatitis

• 81270448 National Natural Science Foundation of China

• Acute liver failure
• Biomarkers
• Plasma exchange
• Proteomics

• Humans
• Liver Failure, Acute/therapy
• Liver Failure, Acute/blood
• Pilot Projects
• Male
• Proteomics/methods
• Female
• Plasma Exchange/methods
• Middle Aged
• Adult

• Awards and Prizes
• Gastroenterology/history
• History, 21st Century
• Humans
• History, 20th Century
• Societies, Medical
• Europe

• type 2 diabetes
• lectins

• Mice
• Humans
• Animals
• Insulin Resistance
• Mice, Obese
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Experimental/metabolism
• AMP-Activated Protein Kinases/metabolism
• Glucose/metabolism
• Obesity/genetics
• Insulin/pharmacology
• Homeostasis
• Anti-Infective Agents/pharmacology

• Agence Nationale de la Recherche (French National Research Agency)
• Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research)
• ALFACT INNOVATION

The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect.

• Glucose uptake
• Insulin resistance
• Skeletal muscles
• Type 2 diabetes

REG3A, a member of the third subclass of the Reg family, has been found in a variety of tissues but is not detected in immune cells. In the past decade, it has been determined that REG3A expression is regulated by injury, infection, inflammatory stimuli, and pro-cytokines via different signaling pathways, and it acts as a tissue-repair, bactericidal, and anti-inflammatory molecule in human diseases. Recently, the role of REG3A in cancer has received increasing attention. The present article aims to investigate the structure, expression, regulation, function of REG3A, and to highlight the potential role of REG3A in tumors.

A detailed literature search and data organization were conducted to find information about the role of REG3A in variety of physiological functions and tumors.

Contradictory roles of REG3A have been reported in different tumor models. Some studies have demonstrated that high expression of REG3A in cancers can be oncogenic. Other studies have shown decreased REG3A expression in cancer cells as well as suppressed tumor growth.

Taken together, better understanding of REG3A may lead to new insights that make it a potentially useful target for cancer therapy.

• Cancer
• Gene expression
• Receptor
• Regenerating protein REG3A
• Regulation
• Signaling pathway

Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.

• AMPK
• NLRP3 inflammasome
• Nrf2
• liver injury
• pancreatitis

Organoids derived from epithelial tumors have recently been utilized as a preclinical model in basic and translational studies. This model is considered to represent the original tumor in terms of 3D structure, genetic and cellular heterogeneity, but not tumor microenvironment. In this study, we established organoids and paired cancer-associated fibroblasts (CAFs) from surgical specimens of colorectal carcinomas (CRCs), and evaluated gene expression profiles in organoids with and without co-culture with CAFs to assess interactions between tumor cells and CAFs in tumor tissues. We found that the expression levels of several genes, which are highly expressed in original CRC tissues, were downregulated in organoids but re-expressed in organoids by co-culturing with CAFs. They comprised immune response- and external stimulus-related genes, e.g., REG family and dual oxidases (DUOXs), which are known to have malignant functions, leading tumor cells to proliferative and/or anti-apoptotic states and drug resistant phenotypes. In addition, the degree of differential induction of REG1 and DUOX2 in the co-culture system varied depending on CAFs from each CRC case. In conclusion, the co-culture system of CRC organoids with paired CAFs was able to partially reproduce the tumor microenvironment.

Liver reduction is the main curative treatment for primary liver cancer, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma.

To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy (90%) and postoperative glucose infusions.

Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%. The animals received a post-operative glucose infusion and were randomly assigned to two groups: One to investigate the survival rate and the other for biochemical analyses. Animals that underwent laparotomy or 70% hepatectomy were used as controls. Blood and liver samples were collected on postoperative days 1 to 7. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, and western blotting.

Postoperative mortality after major resection reached 20% and 55% in the first 24 h and 48 h, respectively, with an overall total of 70% 7 d after surgery. No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers, but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities. Liver regeneration started properly, as early events initiating cell proliferation occurred within the first 3 h, and the G1 to S transition was detected in less than 12 h. However, a rise in p27 (Kip1) followed by p21 (Waf1/Cip1) cell cycle inhibitor levels led to a delayed S phase progression and mitosis. Overall, liver regeneration in rats with a 90% hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis.

This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.

• Major hepatectomy
• Liver failure
• Liver regeneration
• Post-hepatectomy liver failure
• p21
• p27

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3β were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3β expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3β could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

• ALPPS
• JAK2/STAT3 pathway
• Reg3α
• Reg3β
• liver hypertrophy

Hepatocarcinoma‐intestine‐pancreas/pancreatitis‐associated protein (HIP/PAP), a C‐type lectin, exerts anti‐oxidative, anti‐inflammatory, bactericidal, anti‐apoptotic, and mitogenic functions in several cell types and tissues. In this study, we explored the role of HIP/PAP in pulmonary fibrosis (PF). Expression of HIP/PAP and its murine counterpart, Reg3B, was markedly increased in fibrotic human and mouse lung tissues. Adenovirus‐mediated HIP/PAP expression markedly alleviated bleomycin (BLM)‐induced lung injury, inflammation, and fibrosis in mice. Adenovirus‐mediated HIP/PAP expression alleviated oxidative injury and lessened the decrease in pulmonary superoxide dismutase (SOD) activity in BLM‐treated mice, increased pulmonary SOD expression in normal mice, and HIP/PAP upregulated SOD expression in cultured human alveolar epithelial cells (A549) and human lung fibroblasts (HLF‐1). Moreover, in vitro experiments showed that HIP/PAP suppressed the growth of HLF‐1 and ameliorated the H₂O₂‐induced apoptosis of human alveolar epithelial cells (A549 and HPAEpiC) and human pulmonary microvascular endothelial cells (HPMVEC). In HLF‐1, A549, HPAEpiC, and HPMVEC cells, HIP/PAP did not affect the basal levels, but alleviated the TGF‐β1‐induced down‐regulation of the epithelial/endothelial markers E‐cadherin and vE‐cadherin and the over‐expression of mesenchymal markers, such as α‐SMA and vimentin. In conclusion, HIP/PAP was found to serve as a potent protective factor in lung injury, inflammation, and fibrosis by attenuating oxidative injury, promoting the regeneration of alveolar epithelial cells, and antagonizing the pro‐fibrotic actions of the TGF‐β1/Smad signaling pathway.

• HIP/PAP
• fibrosis
• inflammation
• lung
• mouse

Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.

• Reg proteins
• diabetes
• gastrointestinal cancer
• pancreas
• pancreatic adenocarcinoma

• Animals
• Gastrointestinal Hormones/metabolism
• Humans
• Intestinal Mucosa/metabolism
• Pancreatitis-Associated Proteins/metabolism

• P30 DK020572 NIDDK NIH HHS
• R01 DK107652 NIDDK NIH HHS

• Acute hepatic failure
• Gene expression profile
• Hepatocellular carcinoma
• Physiological activities
• Regenerating islet-derived protein

• Animals
• Apoptosis
• Cell Cycle
• Cell Survival
• Female
• Hydrogen Peroxide
• Liver/metabolism
• Liver/pathology
• Liver Failure, Acute/chemically induced
• Liver Failure, Acute/genetics
• Liver Failure, Acute/pathology
• Proto-Oncogene Proteins c-sis/genetics
• Rats
• Rats, Sprague-Dawley
• Up-Regulation

• Bacteria
• IBD
• LPS
• Mouse Model

No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH.

double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately.

57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02).

ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH.

ClinicalTrials.gov NCT01318525

• Acute Disease
• Adult
• Antigens, Neoplasm/adverse effects
• Antigens, Neoplasm/pharmacology
• Antigens, Neoplasm/therapeutic use
• Antioxidants/pharmacokinetics
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Area Under Curve
• Biomarkers, Tumor/adverse effects
• Biomarkers, Tumor/pharmacokinetics
• Biomarkers, Tumor/pharmacology
• Biomarkers, Tumor/therapeutic use
• Double-Blind Method
• Extracellular Matrix/drug effects
• Female
• Humans
• Lectins, C-Type/therapeutic use
• Liver Diseases/drug therapy
• Male
• Middle Aged
• Pancreatitis-Associated Proteins
• Placebos
• Prognosis
• Recombinant Proteins/adverse effects
• Recombinant Proteins/pharmacokinetics
• Recombinant Proteins/pharmacology
• Recombinant Proteins/therapeutic use

• Acetyl-l-carnitine (PubChem CID: 7045767)
• Ammonia
• Carglumic acid (PubChem CID: 121396)
• Cirrhosis
• Glycerol phenylbutyrate (PubChem CID: 10482134)
• Hepatic encephalopathy
• Lactitol (PubChem CID: 157355)
• Lactulose (PubChem CID: 11333)
• Liver failure
• Metabolic disorders
• Rifaximin (PubChem CID: 6436173)
• Sodium benzoate (PubChem CID: 517055)
• Sodium phenylacetate (PubChem CID: 23690424)
• Sodium phenylbutyrate (PubChem CID: 5258)
• Urea cycle
• l-ornithine (PubChem CID: 6262)

TRO40303 is cytoprotective compound that was shown to reduce infarct size in preclinical models of myocardial infarction. It targets mitochondria, delays mitochondrial permeability transition pore (mPTP) opening and reduces oxidative stress in cardiomyocytes submitted to ischemia/reperfusion in vitro. Because the involvement of the mitochondria and the mPTP has been demonstrated in chronic as well as acute hepatitis, we investigated the potential of TRO40303 to prevent hepatocyte injury. A first set of in vitro studies showed that TRO40303 (from 0.3 to 3 μmol/L) protected HepG2 cells and primary mouse embryonic hepatocytes (PMEH) from palmitate intoxication, a model mimicking steatohepatitis. In PMEH, TRO40303 provided similar protection against cell death due to Jo2 anti-Fas antibody intoxication. Further studies were then preformed in a mouse model of Fas-induced fulminant hepatitis induced by injecting Jo2 anti-Fas antibody. When mice received a sublethal dose of Jo2 at 125 μg/kg, TRO40303 pretreatment prevented liver enzyme elevation in plasma in parallel with a decrease in cytochrome C release from mitochondria and caspase 3 and 7 activation in hepatic tissue. When higher, lethal doses of Jo2 were administered, TRO40303 (10 and 30 mg/kg) significantly reduced mortality by 65–90% when administered intraperitoneally (i.p.) 1 h before Jo2 injection, a time when TRO40303 plasma concentrations reached their peak. TRO40303 (30 mg/kg, i.p.) was also able to reduce mortality by 30–50% when administered 1 h postlethal Jo2 intoxication. These results suggest that TRO40303 could be a promising new therapy for the treatment or prevention of hepatitis.

• Acute hepatitis
• acute liver failure
• hepatoprotection
• mitochondria

• Adult
• Aged
• Animals
• Antigens, Neoplasm/metabolism
• Biomarkers, Tumor/metabolism
• Cells, Cultured
• Disease Models, Animal
• Extracellular Matrix/metabolism
• Extracellular Space/metabolism
• Female
• Fibrin/metabolism
• Hepatocytes/metabolism
• Humans
• Lectins, C-Type/metabolism
• Liver Failure, Acute/metabolism
• Liver Failure, Acute/pathology
• Male
• Mice, Inbred C57BL
• Middle Aged
• Models, Biological
• Oxidative Stress
• Pancreatitis-Associated Proteins
• fas Receptor/metabolism

Excitotoxicity plays a significant role in the pathogenesis of perinatal brain injuries. Among the consequences of excessive activation of the N-methyl-d-aspartate (NMDA)-type glutamate are oxidative stress caused by free radical release from damaged mitochondria, neuronal death and subsequent loss of connectivity. Drugs that could protect nervous tissue and support regeneration are attractive therapeutic options. The hepatocarcinoma intestine pancreas protein/pancreatitis-associated protein I (HIP/PAP) or Reg3α, which is approved for clinical testing for the protection and regeneration of the liver, is upregulated in the central nervous system following injury or disease. Here, we examined the neuroprotective/neuroregenerative potential of HIP/PAP following excitotoxic brain injury.

We studied the expression of HIP/PAP and two of its putative effectors, cAMP-regulated phosphoprotein 19 (ARPP19) and growth-associated protein 43 (GAP-43), in the neonatal brain, and the protective/regenerative properties of HIP/PAP in three paradigms of perinatal excitotoxicity: intracerebral injection of the NMDA agonist ibotenate in newborn pups, a pediatric model of traumatic brain injury, and cultured primary cortical neurons.

HIP/PAP, ARPP19, and GAP-43 were expressed in the neonatal mouse brain. HIP/PAP prevented the formation of cortical and white matter lesions and reduced neuronal death and glial activation following excitotoxic insults in vivo. In vitro, HIP/PAP promoted neuronal survival, preserved neurite complexity and fasciculation, and protected cell contents from reactive oxygen species (ROS)-induced damage.

HIP/PAP has strong neuroprotective/neuroregenerative potential following excitotoxic injury to the developing brain, and could represent an interesting therapeutic strategy in perinatal brain injury.

The pancreatitis-associated protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.

We undertook a 12-month prospective study that included 66 Crohn's disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)<3 (UC), along with a normal serum C reactive protein (CRP) and fecal calprotectin. Patients were followed every 3 months. Blood and stool samples were collected and a clinical evaluation was performed at each visit. Serum PAP and CRP levels as well as fecal concentrations of PAP and calprotectin were assessed.

Active CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), p<0.05. No significant change in serum PAP levels in UC and fecal PAP levels in CD and UC were detected during disease activity. In CD, serum PAP was a poor diagnostic predictor of disease activity, with an AUC of 0.69. In patients in remission, fecal PAP was barely detectable in UC compared with CD patients.

Serum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients.

• Adult
• Antigens, Neoplasm/blood
• Biomarkers, Tumor/blood
• C-Reactive Protein/metabolism
• Colitis, Ulcerative/blood
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/physiopathology
• Crohn Disease/blood
• Crohn Disease/diagnosis
• Crohn Disease/physiopathology
• Feces/chemistry
• Female
• Humans
• Lectins, C-Type/blood
• Leukocyte L1 Antigen Complex/metabolism
• Male
• Middle Aged
• Pancreatitis-Associated Proteins
• Prognosis
• Prospective Studies
• Recurrence
• Severity of Illness Index

There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1^+/– mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases.

• Age Factors
• Animals
• Caenorhabditis elegans/physiology
• Female
• Haploinsufficiency/genetics
• Humans
• Longevity/genetics
• Mice
• Mice, Knockout
• Mitochondria/genetics
• Mitochondria/metabolism
• Phenotype
• Proto-Oncogene Proteins c-akt/genetics
• Ribosomes/metabolism

AIM: To examine the expression of nuclear factor κB (NF-κB) and Bcl-2 in non-alcoholic fatty liver disease (NAFLD) in rats and to investigate the role of the mitochondrial injury pathway in hepatocyte apoptosis and the pathogenesis of NAFLD.

METHODS: Thirty-six rats were randomly and equally divided into two groups: a control group and an experimental group. The rats were killed at weeks 6, 10, and 14, and histopathological features of the liver were observed by microscopy. Plasma levels of tumor necrosis factor-α (TNF-α) were measured by radioimmunoassay, hepatocyte apoptosis was assessed by TUNNEL assay, and expression of Bcl-2 and NF-κB proteins in hepatocytes was measured by immunohistochemistry.

RESULTS: Histopathological staining showed the liver structure was normal in the control group. However, lobular steatosis was observed in the model group. Portal and periportal inflammation and lobular inflammation were noted at week 10, and liver fibrosis was visible at week 14. Compared to the control group, apoptosis was increased in the model group, and this process was time-dependent. A time-dependent increase in the expression of Bcl-2 and NF-κB in liver tissue and serum levels of TNF-α was also found in the model group compared to the control group.

CONCLUSION: Apoptosis is a critical step for the development of NAFLD, and NF-κB and Bcl-2 play an important role in hepatocyte apoptosis in NAFLD.

• Nonalcoholic fatty liver disease
• Hepatocyte apoptosis
• Nuclear factor κB
• Bcl-2
• Tumor necrosis factor-α

• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Ceruletide
• Female
• Gene Deletion
• Gene Expression
• Gene Knockdown Techniques
• Lectins, C-Type/genetics
• Lectins, C-Type/metabolism
• Liver/metabolism
• Liver/pathology
• Male
• Mice
• Mice, Knockout
• Pancreas/metabolism
• Pancreas/pathology
• Pancreatitis/metabolism
• Pancreatitis/pathology
• Pancreatitis/prevention & control
• Pancreatitis-Associated Proteins
• STAT3 Transcription Factor/metabolism

• Acetaminophen/toxicity
• Acute Disease
• Animals
• Antigens, Neoplasm/adverse effects
• Antigens, Neoplasm/physiology
• Antigens, Neoplasm/therapeutic use
• Biomarkers, Tumor/adverse effects
• Biomarkers, Tumor/physiology
• Biomarkers, Tumor/therapeutic use
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/etiology
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Hepatitis/drug therapy
• Hepatitis/etiology
• Humans
• Lectins, C-Type/physiology
• Lectins, C-Type/therapeutic use
• Liver Failure/drug therapy
• Liver Regeneration
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Multicenter Studies as Topic
• Pancreatitis-Associated Proteins
• Reactive Oxygen Species/metabolism
• Recombinant Proteins/adverse effects
• Recombinant Proteins/therapeutic use
• fas Receptor/agonists