Inhibition Of Liver Regeneration Research Articles

Serum miR-122 and Human Genomic DNA in Patients With Drug-Induced Acute Liver Failure or With Chronic Hepatitis C

function. Daidzein increased BrdU incorporation to ~30% and prevented hyperbilirubinemia in mice subjected to IR+PHX. While all mice survived after PHX, survival decreased to ~13% after IR+PHX. Daidzein increased survival after IR+PHX to ~88%.Conclusion. Suppression of MB after IR+PHX plays an important role in inhibition of liver regeneration and function. MB is a novel therapeutic target to improve the outcome of MLR (NIDDK).

Myofibroblast depletion does not inhibit liver regeneration after partial hepatectomy

Myofibroblast depletion does not inhibit liver regeneration after partial hepatectomy

Efeitos dos ácidos graxos sobre a regeneração hepática em ratos

To study the effects of polyunsaturated fatty acids (PUFA) omega-3 and omega-6 in the oxidative stress and in liver regeneration in rats subjected to 70% partial hepatectomy (PH, 70% hepatectomy, Higgins-Anderson partial hepatectomy). 72 young male Wistar rats were randomly divided into four equal-sized groups: control (G1), partially hepatectomized (G2), partially hepatectomized with two weeks daily intraperitoneal infusion of omega-3 (G3) and partially hepatectomized with two weeks daily intraperitoneal infusion of omega-6 (G4). In moments 36 h (T1), 168 h (T2) and 336 h (T3) post-PH, thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were measured in plasma and liver tissue, while glucose and total bilirubin were measured in blood. The mass of the residual liver in the same moments was the parameter used to estimate the evolution of liver regeneration. omega-3 PUFA inhibited liver regeneration and induced reduction of hepatic GSH concentration seven days post-PH. Omega-6 PUFA, in contrast, showed no inhibitory effect on regeneration. There was an increase of lipid peroxidation both in blood and liver with administration of omega-6. Omega-3 PUFA retarded post-PH liver regeneration, probably through inhibition of oxidative stress. Omega-6 PUFA increased TBARS concentrations in blood and liver but did not alter the evolution of the liver regenerative process.

Microarray Approach Reveals the Relevance of Interferon Signaling Pathways with Rat Liver Restoration Post 2/3 Hepatectomy at Cellular Level

The immunomodulator interferons are assumed not only to fight tumor progress but also to inhibit liver regeneration by inactivating Kupffer cells. The potential mechanism is still poorly characterized. In particular, the relevance of interferon signaling to liver regeneration at cellular level still remains unknown. In this study, 8 types of rat liver cells from the regenerating liver at 10 recovery time points were separately isolated by percoll density gradient centrifugation and immunomagnetic bead. Transcription profiles of interferon-signaling pathway genes in each cell type along the time course of liver restoration were detected using Rat Genome 230 2.0 Array covering about 12,727 known genes. The chip data demonstrated that hepatocyte mainly up-regulated the IFN-alpha1-mediated JAK/STAT pathway genes; biliary epithelial cell mostly expressed the IFN-beta1-mediated p38 MAPK pathway genes; while the IFN-gamma-activated JAK/STAT pathway genes were down-regulated particularly in HSC, KC, and DC during liver regeneration. It is inferred that STAT3, in contrast to STAT1, seemingly takes a more active role in IFN-alpha1-mediated JAK/STAT pathway in hepatocyte; IFN-beta1-mediated p38 MAPK pathway possibly to some extent affects inflammation and apoptosis of biliary epithelial cell during liver regeneration; IFN-gamma-induced JAK/STAT pathway may be associated with the attenuated apoptosis induction in HSC, KC, and DC. Our data suggested that a better understanding about how interferon signals at liver cell level might be helpful in developing an effective approach to protecting against the inhibition of regeneration.

Suppression of Liver Regeneration and Hepatocyte Proliferation in Hepatocyte-Targeted Glypican 3 Transgenic Mice†

Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. GPC3 is overexpressed in hepatocellular carcinoma. Loss-of-function mutations of GPC3 result in Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by overgrowth of multiple organs, including the liver. Our previous study showed that GPC3 plays a negative regulatory role in hepatocyte proliferation, and this effect may involve CD81, a cell membrane tetraspanin. To further investigate GPC3 in vivo, we engineered transgenic (TG) mice overexpressing GPC3 in the liver under the control of the albumin promoter. GPC3 TG mice with hepatocyte-targeted, overexpressed GPC3 developed normally in comparison with their nontransgenic littermates but had a suppressed rate of hepatocyte proliferation and liver regeneration after partial hepatectomy. Moreover, gene array analysis revealed a series of changes in the gene expression profiles in TG mice (both in normal mice and during liver regeneration). In unoperated GPC3 TG mice, there was overexpression of runt related transcription factor 3 (7.6-fold), CCAAT/enhancer binding protein alpha (2.5-fold), GABA A receptor (2.9-fold), and wingless-related MMTV integration site 7B (2.8-fold). There was down-regulation of insulin-like growth factor binding protein 1 (8.4-fold), Rab2 (5.6-fold), beta-catenin (1.7-fold), transforming growth factor beta type I (3.1-fold), nodal (1.8-fold), and yes-associated protein (1.4-fold). Changes after hepatectomy included decreased expression in several cell cycle-related genes. Our results indicate that in GPC3 TG mice, hepatocyte overexpression of GPC3 suppresses hepatocyte proliferation and liver regeneration and alters gene expression profiles, and potential cell cycle-related proteins and multiple other pathways are involved and affected.

Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-α-dependent mechanism

Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN-gamma. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl(4))-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl(4) model. Administration of poly I:C suppressed liver regeneration in CCl(4)-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl(4)-treated mice. Poly I:C and CCl(4) cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFN-gamma and tumor necrosis factor (TNF)-alpha. Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl(4) treatment. Finally, blockage of TNF-alpha but not IFN-gamma restored liver regeneration in poly I:C/CCl(4)-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl(4)-induced liver injury model via induction of NK cell production of TNF-alpha.

The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats

Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling. Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture. Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*>70%PH*>normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment. Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.

Effect and Risk of AEE788, a Dual Tyrosine Kinase Inhibitor, on Regeneration in a Rat Liver Resection Model

Background: AEE788, a dual tyrosine kinase inhibitor, has antiproliferative effects on diverse tumor models in mice. We aimed to investigate whether AEE788 blocks liver regeneration and causes drug-related side effects. Methods: Rats treated orally with 50 mg/kg AEE788 or solvent every 2 days were subjected to 70% partial hepatectomy (PH) and sacrificed on postoperative days 1, 2, 7, and 28. Liver regeneration was evaluated using liver weight to body weight ratio, BrdU-staining, mitotic index, and PCR for PCNA (proliferating cell nuclear antigen). Side effects on the gastrointestinal system and liver were assessed using clinical chemistry, histology, silver staining, and immunohistochemistry. Plasma and liver tissue levels of AEE788 were measured using spectrometry. Results: AEE788 treatment did not inhibit liver regeneration. No obvious drug-related systemic or hepatic side effects were observed. Restoration of liver architecture during liver regeneration was not obviously impaired, even after 4 weeks’ AEE788 treatment. After a 1-week treatment, AEE788 concentrations in plasma and liver tissue in the PH group were 3-fold and 8-fold higher than the non-PH group, respectively. Conclusion: Its antiproliferative properties, good tolerance, and lack of inhibition on liver regeneration make AEE788 a potential candidate for clinical study with oncological PH, but one that carries the risk of overexposure in the early postoperative phase.

Cytokine-dependent activation of small hepatocyte-like progenitor cells in retrorsine-induced rat liver injury

Complete liver regeneration after partial hepatectomy (PH) in rats exposed to the pyrrolizidine alkaloid retrorsine is accomplished through the activation, expansion, and differentiation of a population of small hepatocyte-like progenitor cells (SHPCs). The mechanism(s) governing activation of SHPCs after PH in retrorsine-injured rats has not been investigated. We examined the possibility that SHPCs require cytokine priming prior to becoming growth factor responsive in this model of liver injury and regeneration. Male Fischer 344 rats were treated with retrorsine (30 mg/kg ip) at 6 and 8 weeks of age. Retrorsine-exposed and age-matched control rats were randomized into dexamethasone-treated and no DEX groups. DEX-treated animals were either given a single dose of DEX (2 mg/kg ip) at the time of PH or multiple DEX treatments (2 mg/kg ip each) at 24 and 1 h before PH and 1, 2, and 3 days post-PH. A subset of rats received 10 μg of recombinant IL6 protein, administered intravenously 30 min after PH. Liver tissues were harvested at 7, 14, 21, and 30 days post-PH. Treatment of retrorsine-exposed rats with the cytokine inhibitor dexamethasone (DEX) effectively blocked the emergence of SHPCs resulting in an inhibition of liver regeneration and producing significant short-term mortality. The livers of DEX-treated retrorsine-exposed rats displayed decreased numbers and smaller SHPC clusters compared to retrorsine-exposed rats in the absence of DEX treatment. Administration of recombinant IL6 to DEX-treated retrorsine-exposed rats restored the emergence of SHPCs and SHPC-mediated regenerative response. The livers of DEX-treated retrorsine-exposed rats that received IL6 displayed numbers of expanding SHPC clusters comparable to that of retrorsine-exposed rats in the absence of DEX treatment. These results combine to suggest that SHPC activation after PH in retrorsine-exposed rats is cytokine dependent and may specifically require IL6.

The Age-Associated Decline of Glycogen Synthase Kinase 3β Plays a Critical Role in the Inhibition of Liver Regeneration

Aging reduces the regenerative capacities of many tissues. In this paper, we show a critical role of the glycogen synthase kinase 3beta (GSK3beta)-cyclin D3 pathway in the loss of the regenerative capacity of the liver. In young animals, high levels of growth hormone (GH) increase expression of GSK3beta, which associates with cyclin D3 and triggers degradation of cyclin D3. In livers of old mice, the GSK3beta promoter is repressed by C/EBPbeta-histone deacetylase 1 (HDAC1) complexes, leading to the reduction of GSK3beta. The treatment of old mice with GH increases expression of GSK3beta via removal of the C/EBPbeta-HDAC1 complexes from the GSK3beta promoter. We found that the GSK3beta-cyclin D3 pathway is also altered in young GH-deficient Little mice and that treatment of Little mice with GH corrects the GSK3beta-cyclin D3 pathway. We present evidence that GSK3beta regulates liver proliferation by controlling growth-inhibitory activity of C/EBPalpha. The downregulation of GSK3beta in young mice inhibits liver proliferation after partial hepatectomy via the cyclin D3-C/EBPalpha pathway, while the elevation of GSK3beta in old mice accelerates liver proliferation. Thus, this paper shows that GSK3beta is a critical regulator of liver proliferation and that the reduction of GSK3beta with age causes the loss of regenerative capacities of the liver.

Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases

Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-gamma. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-gamma and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed.Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease.

Postoperative liver function recovery after hepatic resection for colorectal metastases previously treated with bevacizumab

4093 Background: The influence of bevacizumab on postoperative morbidity in patients with colorectal liver metastases (CLM) submitted to hepatectomy has been evaluated. However, in spite of a potential inhibition of liver regeneration, its impact on postoperative liver function recovery remains unknown. Methods: From July 2005 to December 2007, we evaluated 37 patients treated with bevacizumab prior to hepatectomy. Postoperative evolution of liver function variables was compared with that of 70 bevacizumab-naïve patients. Recorded parameters included prothrombin time, serum aspartate and alanine aminotransferase levels, and serum gamma-glutamyltransferase and total bilirubin levels. Results: Most patients of the bevacizumab group received 1 line of chemotherapy (62% vs 54% in the control group) (P=0.43). Bevacizumab was combined to 5-fluorouracil (5-FU), leucovorin (LV) and irinotecan or 5-FU, LV and oxaliplatin in the last preoperative line, in 57% and 30% of cases, respectively. Patients received a mean total number of 10.4+5.7 and 11.1+6.2 cycles of preoperative chemotherapy in the bevacizumab and control group (P=0.56). The median number of administered bevacizumab cycles was 6 (range: 3–25). Bevacizumab administration was stopped at a median of 7.9 weeks before surgery (range: 3.6–18.0). Major hepatectomies were performed in 41% and 36% of bevacizumab and control patients, respectively (P=0.62). Baseline liver function tests as well as postoperative liver function recovery were similar between patients treated with or without bevacizumab (Table). Postoperative morbidity occurred in 35% of bevacizumab patients and in 43% of control patients (P=0.44). Conclusions: Preoperative bevacizumab treatment has no impact on short-term liver function recovery after hepatic resection for CLM and has no deleterious effect on the incidence of postoperative morbidity. [Table: see text] No significant financial relationships to disclose.

A Critical Role for Matrix Metalloproteinases in Liver Regeneration

Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary MMP activity. Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum MMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined. The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P < 0.001). Urinary MMP-9 activity was elevated during hepatic regeneration, and decreased on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from hepatectomy Marimastat mice, in which liver regeneration was successfully inhibited, showed consistently low levels of MMP-2 and MMP-9 activity. The hepatectomy Marimastat group also exhibited elevated serum IL-6 levels on post-operative day 8, while serum TNF-alpha soluble receptor II levels were unchanged. Hepatocyte growth factor levels were not significantly different between the control hepatectomy and hepatectomy Marimastat groups at days 2, 4, and 8. Liver microvessel density was reduced in the hepatectomy Marimastat group at day 4. Mitotic index and proliferating cell nuclear antigen index were significantly decreased in the Marimastat hepatectomy group at post-operative day 2. The broad-spectrum MMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum MMP-inhibitor Marimastat.

Gene modulation associated with inhibition of liver regeneration in hepatitis B virus X transgenic mice

To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X (HBx)-expressing transgenic mice. Microarray technology was performed on liver tissue obtained from 4 control (LacZ) and 4 transgenic mice (HBx-LacZ), 48 h after partial hepatectomy. The significance of the normalized log-ratios was assessed for each gene, using robust t-tests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR. The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins (Rad-52, MSH6) and transmembrane proteins (syndecan 4, tetraspanin), while down-regulated genes were connected to the regulation of transcription (histone deacetylase, Zfp90, MyoD1) and were involved in the cholesterol metabolic pathway and isoprenoid biosynthesis (farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3). Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration.

Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice

A fraction of HBV carriers have a risk to develop liver cancer. Because liver possesses a strong regeneration capability, surgical resection of cancerous liver or transplantation with healthy liver is an alternate choice for HBV-caused hepatocarcinoma therapy. How HBV infection affects the regeneration of hepatectomized or transplanted liver remains elusive. We report that partial hepatectomy (PHx)-induced liver regeneration was reduced in HBV transgenic (HBV-tg) mice, a model of human HBV infection. PHx markedly triggered natural killer T (NKT) cell accumulation in the hepatectomized livers of HBV-tg mice, simultaneously with enhanced interferon gamma (IFN-gamma) production and CD69 expression on hepatic NKT cells at the early stage of liver regeneration. The impairment of liver regeneration in HBV-tg mice was largely ameliorated by NKT cell depletion, but not by natural killer (NK) cell depletion. Blockage of CD1d-NKT cell interaction considerably alleviated NKT cell activation and their inhibitory effect on regenerating hepatocytes. Neutralization of IFN-gamma enhanced bromodeoxyuridine incorporation in HBV-tg mice after PHx, and IFN-gamma mainly induced hepatocyte cell cycle arrest. Adoptive transfer of NKT cells from regenerating HBV-tg liver, but not from normal mice, could inhibit liver regeneration in recipient mice. Activated NKT cells negatively regulate liver regeneration of HBV-tg mice in the PHx model.

5: Targeted knockdown of PI3K components with small interfering RNA (siRNA) inhibits liver regeneration following partial hepatectomy

Introduction: Hepatectomy is associated with rapid regeneration, macrophage infiltration, and Kupffer cell hyperplasia and hypertrophy within the remnant liver; signaling pathways responsible for this process have not been clearly delineated. Phosphatidylinositol-3 kinase (PI3K), consisting of p85α regulatory and p110α catalytic subunits, regulates multiple cellular processes, including cell growth, cell survival, and leukocyte migration. We have previously demonstrated that inhibition of the PI3K pathway significantly inhibits stimulated growth of the pancreas and intestinal mucosa.

β‐Catenin is essential for liver regeneration following acetaminophen‐induced acute liver failure.

Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF). Understanding the mechanisms of liver regeneration following APAP-induced liver injury are of high therapeutic relevance. To investigate the role of Wnt/β-catenin, an important pathway in liver biology, in liver regeneration after APAP-induced ALF, male CD-1 mice were treated with a non-lethal dose of APAP (500 mg/kg), which induced extensive liver injury and subsequent regeneration. Rapid induction in the total and active β-catenin was evident at 1–3 hr after APAP treatment, along with its nuclear translocation at 6 hr. Further studies revealed that both canonical (GSK-3β-dependent) and non-canonical (c-met-dependent) pathways were involved in β-catenin activation. Administration of a lethal dose of APAP (700 mg/kg) known to inhibit liver regeneration completely suppressed β-catenin activation. Further, β-catenin conditional knockout mice, which have low CYP2E1 expression, exhibited increased APAP-mediated injury and decreased cell proliferation following CYP2E1 induction. Furthermore, suppression of β-catenin activation was observed in human APAP-induced ALF liver samples along with suppression of liver regeneration. Taken together, these data indicate that β-catenin activation plays an important role in stimulation of liver regeneration following APAP overdose and might have therapeutic and prognostic implications in APAP ALF.

Involvement of alcohol and aldehyde dehydrogenase activities on hepatic retinoid metabolism and its possible participation in the progression of rat liver regeneration

Liver alcohol dehydrogenase (ADH) activity is decreased towards exogenous substrates after partial hepatectomy (PH), probably due to putative endogenous substrates acting as ADH inhibitors. Hence, retinoids could be suitable candidates as such endogenous substrates. Therefore, cytosolic ADH kinetic analysis using several substrates, liver cytosolic and mitochondrial aldehyde dehydrogenase (ALDH) activities, retinal and retinol content, as well as expression of proteins for ADH and CRBPI (a retinol carrier protein) were determined in liver samples, at two stages of liver regeneration (one- or two-thirds PH). The effect of inhibiting in vivo liver ADH by 4-methylpyrazole (4-MP) was also evaluated after 70%-PH. With 70%-PH, in vitro ADH activity towards exogenous alcohols and aldehydes was diminished, but retinol oxidation was increased and retinal reduction was decreased. These activities that be due to the participation of an ADH type which did not correlate with the amount of immunoreactive ADH protein. Cytosolic and mitochondrial ALDH activities oxidized actively retinal, whereas retinol and CBRP-I expression were reduced in these animals. With 30%-PH, these changes were less evident and sometimes opposite to those found with 70%-PH. In addition, retinol readily inhibited ADH-mediated ethanol oxidation. Interestingly, in vivo 4-MP administration inhibited ADH activity in a dose-dependent manner correlating with a progressive inhibition of liver regeneration. In conclusion, PH-induced inhibition of ADH (mainly type I) seems to be related to ADH-mediated retinoid metabolism during liver proliferation. Thus, results suggest a role of ADH in retinoid metabolism, which is apparently required during rat liver regeneration.

Nonalcoholic Fatty Liver Disease: Cytokine-Adipokine Interplay and Regulation of Insulin Resistance

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

The importance of platelet-derived serotonin in mediating hepatic regeneration

Platelet-derived serotonin mediates liver regeneration. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA. Platelet-derived serotonin mediates liver regeneration. The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration. [Abstract reproduced by permission of Science 2006;312:104–107].