Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration.

ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown. We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx).

Yes-associated protein promotes early hepatocyte cell cycle progression in regenerating liver after tissue loss.

The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo-YAP1 pathway, a key controller of organ size. Yes-associated protein 1 (YAP1)-a growth effector usually restrained by Hippo signaling-is believed to be of particular importance; however, its role in liver regeneration remains ill-defined. To explore its function, we knocked down YAP1 prior to standard 70%-hepatectomy (sHx) using a hepatocyte-specific nanoformulation.

Exercise Improves Outcomes of Surgery on Fatty Liver in Mice: A Novel Effect Mediated by the AMPK Pathway.

Objective: To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs.

Summary Of Background Data: Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown.

Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration.

The liver is the only organ in mammals that fully regenerates even after major injury. To identify orchestrators of this regenerative response, we performed quantitative large-scale proteomics analysis of cytoplasmic and nuclear fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly upregulated after two-third hepatectomy, with the ubiquitin ligase Nedd4-1 being a top hit.

The Allosteric Hemoglobin Effector ITPP Inhibits Metastatic Colon Cancer in Mice.

Objective: To test the effects of enhanced intracellular oxygen contents on the metastatic potential of colon cancer.

Background: Colorectal cancer is the commonest gastrointestinal carcinoma. Distant metastases occur in half of patients and are responsible for most cancer-related deaths.

PTEN Down-Regulation Promotes β-Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice.

Unlabelled: In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is a key inhibitor of the protein kinase B/mammalian target of rapamycin axis that regulates growth and metabolic adaptations after hepatectomy.

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate.

Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.

Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis.

Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss.

Background & Aims: Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for-size-syndrome (SFSS). The molecular processes underlying liver failure are ill-understood.

The constitutive androstane receptor activator 4-[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline inhibits the gluconeogenic genes PEPCK and G6Pase through the suppression of HNF4α and FOXO1 transcriptional activity.

Background And Purpose: The dual role of the constitutive androstane receptor (CAR) as both a xenosensor and a regulator of endogenous energy metabolism (lipogenesis and gluconeogenesis) has recently gained acceptance. Here, we investigated the effects of 4-[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline (transpDMA), an effective CAR activator, on the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in rat livers.

Experimental Approach: The effects of transpDMA were investigated in normal and high-fat diet-fed Wistar rats using real-time PCR, Western blotting, chromatin immunoprecipitation assays (ChIP), glucose tolerance test and insulin tolerance test.

Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes.

The constitutive androstane receptor (CAR, NR1I3) has a central role in detoxification processes, regulating the expression of a set of genes involved in metabolism. The dual role of NR1I3 as both a xenosensor and as a regulator of endogenous energy metabolism has recently been accepted. Here, we investigated the mechanism of transcriptional regulation of the glucose metabolising genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by the cis isomer of 2,4,6-triphenyldioxane-1,3 (cisTPD), a highly effective NR1I3 activator in rat liver.

Constitutive androstane receptor (CAR) is a xenosensor and target for therapy.

Constitutive androstane receptor (CAR, NR1I3), which is under consideration in this review, is a member of the superfamily of nuclear receptors. However, certain features distinguish CAR from the variety of nuclear receptors. First, this receptor has structural features that allow it to display constitutive activity in the absence of a ligand and to interact in a species-specific manner with a huge number of ligands diverse in chemical structure and origin.

Effect of several analogs of 2,4,6-triphenyldioxane-1,3 on constitutive androstane receptor activation.

2,4,6-Triphenyldioxane-1,3 (TPD) is a highly effective species-specific inducer of CYP2В in rats. Several analogs of TPD were synthesized to verify a hypothesis that minor changes in the inducer structure can cause changes in induction abilities (R=H, cisTPD and transTPD; R=N(CH(3))(2), transpDMA; R=NO(2), transpNO(2); R=F, transpF; R=OCH(3), transpMeO). Five of six compounds were able to activate CAR in rat liver.