cyclin-d1 and Fatty-Liver

Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%). Animals underwent diet withdrawal to control chow and/or underwent ischemia reperfusion and partial hepatectomy injury (I/R-PHx) and reperfused out to 7 days on control chow. For animals with severe macrosteatosis, hepatic levels of IL-33 decreased while Cyclin D1 levels increased in the absence of NF-κB p65 phosphorylation. Animals with high levels of nuclear Cyclin D1 prior to I/R-PHx either did not survive or had persistent macrosteatosis after 7 days on control chow. Survival 7 days after I/R-PHx fell to 57% which correlated with increased Cyclin D1 and decreased liver IL-33 levels. In the absence of I/R-PHx, withdrawing the MCD diet normalized IL-33, Cyclin D1 levels, and I/R-PHx survival back to baseline. In transplanted grafts with macrosteatosis, higher Cyclin D1 mRNA expression was observed. Shifts in Cyclin D1 and IL-33 expression may identify severely macrosteatotic livers with increased failure risk if subjected to I/R injury. Clinical validation of the panel in donor grafts with macrosteatosis revealed increased Cyclin D1 expression corresponding to delayed graft function. This pre-surgical biomarker panel may identify the subset of livers with increased susceptibility to PNF.

Topics: Adult; Animals; Biomarkers; Cyclin D1; Diet; Disease Models, Animal; Disease Susceptibility; Fatty Liver; Humans; Interleukin-33; Liver; Liver Failure; Liver Transplantation; Male; Middle Aged; Rats, Wistar; Reperfusion Injury; Survival Analysis

Impaired fatty liver regeneration has already been reported in many genetic modification models. However, in diet-induced simple hepatic steatosis, which showed similar phenotype with clinical pathology, whether liver regeneration is impaired or not remains unclear. In this study, we evaluated liver regeneration in mice with diet-induced simple hepatic steatosis, and focused on excess lipid accumulation occurring during liver regeneration.. Mice were fed high fat diet (HFD) or control diet for 9-10 weeks. We analyzed intrahepatic lipid accumulation, DNA replication, and various signaling pathways including cell proliferation and ER stress during liver regeneration after partial hepatectomy. In addition, some of mice were pretreated with tauroursodeoxycholic acid (TUDCA), a chemical chaperone which alleviates ER stress, and then we estimated TUDCA effects on liver regeneration.. The peak of hepatocyte BrdU incorporation, the expression of proliferation cell nuclear antigen (PCNA) protein, and the expressions of cell cycle-related genes were observed in delayed time in HFD mice. The expression of phosphorylated Erk1/2 was also delayed in HFD mice. The amounts of liver triglyceride were at least twofold higher in HFD mice at each time point. Intrahepatic palmitic acid was increased especially in HFD mice. ER stress induced during liver regeneration was significantly higher in HFD mice. In HFD mice, pretreatment with TUDCA reduced ER stress and resulted in improvement of delayed liver regeneration.. In simple hepatic steatosis, lipid overloading occurring during liver regeneration might be caused ER stress and results in delayed hepatocyte DNA replication.

Topics: Animals; Cell Proliferation; Cholagogues and Choleretics; Cyclin A2; Cyclin B1; Cyclin D1; Cyclins; Diet, High-Fat; DNA Replication; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; Forkhead Box Protein M1; Forkhead Transcription Factors; Gene Expression; Heat-Shock Proteins; Hepatectomy; Hepatocytes; Liver Regeneration; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Organ Size; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Regulatory Factor X Transcription Factors; RNA, Messenger; Stress, Physiological; Taurochenodeoxycholic Acid; Time Factors; Transcription Factors; Unfolded Protein Response

Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo.. Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat.. The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-alpha and procollagen alpha (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n = 1/8), whereas no tumor was detected in WT mice (n = 10).. Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis.

Topics: Adenoma; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Collagen Type I; Collagen Type I, alpha 1 Chain; Cyclin D1; Dietary Fats; Disease Models, Animal; Disease Progression; Fatty Liver; Hyperlipidemias; Hyperplasia; Liver; Liver Cirrhosis, Experimental; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; RNA, Messenger; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF) has pleiotropic effects including on hepatic metabolism. Here we investigated the effect of high cholesterol diet (1.25%) in TNF deficient mice. TNFalpha/beta deficient mice developed hepatomegaly and extensive steatosis in the absence of steatohepatitis as compared to wild type mice. Saturated and unsaturated, prominently mono- but also poly-unsaturated fatty acids (MUFA, PUFA) prevailed in steatotic livers. Down-regulation of the cholesterol scavenger receptor B1 and reduced insulin induced phosphorylation of protein kinase B in cholesterol fed TNFalpha/beta deficient mice likely contributed to the development of hepatic steatosis, which was accompanied by increased body weight and bone length. Steatosis was only present in TNFalpha/beta double deficient mice, however not in single TNF deficient mice suggesting a redundant role of TNFalpha and TNFbeta. In conclusion, high cholesterol diet causes an abnormal metabolic phenotype in the simultaneous absence of both TNFalpha and beta signals. The presence of either TNFalpha or beta alone is sufficient to reconstitute the control of lipid homeostasis.

Topics: Animals; Aorta; Cholesterol, Dietary; Cyclin D1; Fatty Acids; Fatty Liver; Hepatomegaly; Insulin; Liver; Lymphotoxin-alpha; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Organ Size; Phosphorylation; Proto-Oncogene Proteins c-akt; Scavenger Receptors, Class B; Tumor Necrosis Factor-alpha

Profound impairment of liver regeneration in rodents with dysfunctional leptin signaling has been attributed to non-alcohol-induced fatty liver disorders (NAFLD). Our aim was to establish whether defective liver regeneration in ob/ob mice is a direct consequence of leptin-dependent, intracellular signaling mechanisms controlling cell-cycle regulation in hepatocytes.. After exposure to a single hepatotoxic dose of (CCl(4)), the regenerative response to hepatic injury was studied in leptin-deficient ob/ob and control mice. The effects of leptin supplementation (100 microg x kg(-1) x day(-1)) were examined. We assessed entry into and progression through the cell cycle and activation of key signaling intermediates and transcriptional regulators.. CCl(4)-induced liver injury was equally severe in ob/ob and control mice. In leptin-deficient mice, it was associated with exaggerated activation of NF-kappa B and STAT3 during the priming phase, abrogation of tumor necrosis factor (TNF) and interleukin (IL)-6 release at the time of G1/S transition, and failure of hepatocyte induction of cyclin D1 and cell cycle entry. Leptin replacement corrected these defects in ob/ob mice by restoring TNF and IL-6 release and inducing cyclin D1. Hepatocytes entered S phase and progressed, as in wild-type mice, to vigorous mitosis and normal hepatic regenerative response. In ob/ob mice, low doses of TNF before CCl(4) also were associated with restitution of TNF release and proliferative capabilities.. Impaired liver regeneration in ob/ob mice is caused by leptin deficiency. We propose that altered cytokine production in ob/ob mice is part of the mechanisms responsible for impaired proliferation in response to hepatic injury.

Topics: Animals; Carbon Tetrachloride; Cell Division; Chemical and Drug Induced Liver Injury; Cyclin D1; Fatty Liver; Interleukin-6; Leptin; Liver; Liver Regeneration; Mice; Mice, Inbred C57BL; Mice, Obese; Necrosis; Proliferating Cell Nuclear Antigen; Recombinant Proteins; Signal Transduction; Tumor Necrosis Factor-alpha

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPAR gamma and PPAR gamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.

Topics: 3T3 Cells; Animals; Breast; Breast Neoplasms; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Cyclin D1; Ecdysterone; Epithelial Cells; Fatty Liver; Female; Gene Expression Regulation; Humans; Mice; Mice, Mutant Strains; Mice, Transgenic; Models, Molecular; Mutation; Protein Conformation; Receptors, Cytoplasmic and Nuclear; Reference Values; Repressor Proteins; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation