Liver Growth Research Articles

Low salinity affects cellularity, DNA methylation, and mRNA expression of igf1 in the liver of half smooth tongue sole (Cynoglossus semilaevis).

Animal growth depends on feedback regulation of hormone levels and environmental conditions. Insulin-like growth factor-1 (Igf1) promotes cell growth and differentiation and represses apoptosis and is highly regulated by the environment. Moreover, animals modify physiological homeostasis under stressful conditions through epigenetics and genetic regulatory mechanisms. Therefore, a comprehensive understanding of the effects of salt on fish growth is needed. In this study, half smooth tongue sole (Cynoglossus semilaevis) were subjected to 15‰ salinity for 0, 7, and 60days (D) to assess the effects of low salinity on liver cellularity and growth. The results show that low salinity changed liver morphology, suggesting an increase in energy expenditure to recover from the osmotic disruption. igf1 was upregulated in female fish under 15‰ salinity after 7D and may participate in molecular repair. igf1 was downregulated after 60D of salt stress, resulting in retarded growth. Methylation levels were opposite to those of gene expression, suggesting inhibited regulation. Furthermore, three exons in the igf1 gene had significantly different methylation levels in fish under salt stress. Notably, more putative transcription factor binding sites were located in CpG sites at higher methylation levels. igf1 is not a sex-related gene, as no difference in methylation level was detected between males and females in the control group. These results clarify liver damage and changes in DNA methylation and mRNA expression of igf1, providing insight into the adverse effects of low salt on growth of C. semilaevis and the epigenetics and regulatory mechanisms involved in stressful conditions.

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

PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908-921).

Aflatoxins occurrence through the food chain in Costa Rica: Applying the One Health approach to mycotoxin surveillance

Aflatoxins (AFs) are toxic metabolites produced by Aspergillus spp. and commonly found in crops, grains, feedstuff, and forages. Exposure to AFs has been associated with increased risk of liver cancer and growth retardation in humans, liver damage, immunosuppression, embryotoxicity in both animals and humans, and decreased milk, egg and meat production in animals. For the first time, the Costa Rican national mycotoxin surveillance programs for animal feed and food are considered as a whole, applying the One Health approach to the mycotoxin epidemiological research. Therefore, the aim of this study was to determine the occurrence of AFs in cereals, nuts, grains intended for animal and human consumption in Costa Rica.In animal feed and feed ingredients, 970 samples were analyzed for AFs from 2010 to 2016 with an overall prevalence of positive samples of 24.0% (ranging from 0.01 to 290 μg kg−1). Only 2.5% of the samples failed to comply the regulation for total AFs (20 μg kg−1 feed). From 5493 samples of agricultural commodities intended for human consumption analyzed from 2003 to 2015, there was an overall prevalence of AF positive samples of 10.8% (ranging from 0.48 to 500 μg kg−1), and 2.8% did not comply the regulation for AFs (20 μg kg−1). In both feed and food, the highest AF prevalence corresponded to corn ingredients (27.8%) and white corn (38.6%), respectively. Among the commodities intended for human consumption, red beans had the highest aflatoxin concentrations (500 μg kg−1).

Establishment of a mice model with liver-specific AMP-activated protein kinase gene knockout

AMP-activated protein kinase (AMPK) is involved in the development and progression of tumors including hepatocellular carcinoma (HCC). However, studies on AMPK and tumorigenesis were largely based on experiments in vitro or tumor xenografts model. Here, we introduce a liver-specific AMPKα1 knockout mice model, which is achieved by Alb-Cre recombinase system. The expression of AMPKα1 in the liver of AMPKα1 -/--Alb-Cre mice is absent. AMPKα1 knockout in the liver does not affect the growth and histological structure of mouse liver. This model provides a favorable tool to the study of the roles of AMPKα1 in liver metabolism or tumorigenesis.

In-ovo monochromatic green light photostimulation enhances embryonic somatotropic axis activity

Previous studies demonstrated that in ovo photostimulation with monochromatic green light increases body weight and accelerates muscle development in broilers. The mechanism in which in ovo photostimulation accelerates growth and muscle development is not clearly understood. The objective of the current study was to define development of the somatotropic axis in the broiler embryo associated with in ovo green light photostimulation. Two-hundred-forty fertile broiler eggs were divided into 2 groups. The first group was incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W\m2 at shell level, and the second group was incubated under dark conditions and served as control. In ovo green light photostimulation increased plasma growth hormone (GH) and prolactin (PRL) levels, as well as hypothalamic growth hormone releasing hormone (GHRH), liver growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-1) mRNA levels. The in ovo photostimulation did not, however, increase embryo's body weight, breast muscle weight, or liver weight. The results of this study suggest that stimulation with monochromatic green light during incubation increases somatotropic axis expression, as well as plasma prolactin levels, during embryonic development.

MiR-145 mediates zebrafish hepatic outgrowth through progranulin A signaling.

MicroRNAs (miRs) are mRNA-regulatory molecules that fine-tune gene expression and modulate both processes of development and tumorigenesis. Our previous studies identified progranulin A (GrnA) as a growth factor which induces zebrafish hepatic outgrowth through MET signaling. We also found that miR-145 is one of potential fine-tuning regulators of GrnA involved in embryonic hepatic outgrowth. The low level of miR-145 seen in hepatocarinogenesis has been shown to promote pathological liver growth. However, little is known about the regulatory mechanism of miR-145 in embryonic liver development. In this study, we demonstrate a significant decrease in miR-145 expression during hepatogenesis. We modulate miR-145 expression in zebrafish embryos by injection with a miR-145 mimic or a miR-145 hairpin inhibitor. Altered embryonic liver outgrowth is observed in response to miR-145 expression modulation. We also confirm a critical role of miR-145 in hepatic outgrowth by using whole-mount in situ hybridization. Loss of miR-145 expression in embryos results in hepatic cell proliferation, and vice versa. Furthermore, we demonstrate that GrnA is a target of miR-145 and GrnA-induced MET signaling is also regulated by miR-145 as determined by luciferase reporter assay and gene expression analysis, respectively. In addition, co-injection of GrnA mRNA with miR-145 mimic or MO-GrnA with miR-145 inhibitor restores the liver defects caused by dysregulation of miR-145 expression. In conclusion, our findings suggest an important role of miR-145 in regulating GrnA-dependent hepatic outgrowth in zebrafish embryonic development.

Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns?

BackgroundLiver stem cell therapy (SCT) has been suggested as a promising means to improve liver regeneration in advanced liver disease. However, data from trials are heterogeneous, with no systematic histological evaluation. The aim of this study is to specifically analyze the effect of autologous SCT on liver regeneration and on gene expression changes.MethodsIndividuals in the randomized controlled trial of SCT in alcoholic hepatitis with paired liver biopsies were included (n = 58). Immunohistochemistry (Ki67, K7, and CD68), in situ hybridization (SPINK1), and global gene expression analysis were performed on liver biopsies (30 control patients and 28 patients with transarterial administration of bone marrow-derived stem cells) both at baseline and after 4 weeks of follow-up.ResultsNo difference between the two groups could be observed regarding the proliferative hepatocyte number, proliferative K7-positive cells, or total K7-positive cells at the 4-week follow-up liver biopsy. However, patients who received SCT showed a more important liver macrophagic expansion as compared to standard treatment. Transcriptome data revealed changes in genes linked with inflammation (CD68 and SAA), regeneration (SPINK1 and HGF), fibrosis (COL1A1), and stem cells (CD45). No changes in gene pathways involved in liver growth and cell cycle proteins were evident. SPINK1 mRNA was present by in situ hybridization at week 4 in SCT patients in the liver parenchyma areas adjacent to macrophage recruitment and liver cell proliferation.ConclusionsThe analysis of liver tissue after SCT demonstrated an expansion of macrophages concurrent with an upregulated expression of genes involved in inflammatory and regenerative pathways. With the negative results from the clinical trial, the impact of the SCT has to be interpreted as weak, and it is not able to modify the clinical course of this severe liver disease.

Aflatoxin levels in sunflower seeds and cakes collected from micro- and small-scale sunflower oil processors in Tanzania.

Aflatoxin, a mycotoxin found commonly in maize and peanuts worldwide, is associated with liver cancer, acute toxicosis, and growth impairment in humans and animals. In Tanzania, sunflower seeds are a source of snacks, cooking oil, and animal feed. These seeds are a potential source of aflatoxin contamination. However, reports on aflatoxin contamination in sunflower seeds and cakes are scarce. The objective of the current study was to determine total aflatoxin concentrations in sunflower seeds and cakes from small-scale oil processors across Tanzania. Samples of sunflower seeds (n = 90) and cakes (n = 92) were collected across two years, and analyzed for total aflatoxin concentrations using a direct competitive enzyme-linked immunosorbent assay (ELISA). For seed samples collected June-August 2014, the highest aflatoxin concentrations were from Dodoma (1.7–280.6 ng/g), Singida (1.4–261.8 ng/g), and Babati-Manyara (1.8–162.0 ng/g). The highest concentrations for cakes were from Mbeya (2.8–97.7 ng/g), Dodoma (1.9–88.2 ng/g), and Singida (2.0–34.3 ng/g). For seed samples collected August-October 2015, the highest concentrations were from Morogoro (2.8–662.7 ng/g), Singida (1.6–217.6 ng/g) and Mbeya (1.4–174.2 ng/g). The highest concentrations for cakes were from Morogoro (2.7–536.0 ng/g), Dodoma (1.4–598.4 ng/g) and Singida (3.2–52.8 ng/g). In summary, humans and animals are potentially at high risk of exposure to aflatoxins through sunflower seeds and cakes from micro-scale millers in Tanzania; and location influences risk.

383 - Physiology of Alpps: Liver Growth after Portal Vein Ligation Correlates with the Degree of Neo-Collateralization between the Growing Lobe and the Deportalized Liver

383 - Physiology of Alpps: Liver Growth after Portal Vein Ligation Correlates with the Degree of Neo-Collateralization between the Growing Lobe and the Deportalized Liver

Mo1362 - Annual Rate of Growth in Total Liver and Kidney Volume is a Novel Parameter when Assessing Symptom Burden from Liver Cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Mo1362 - Annual Rate of Growth in Total Liver and Kidney Volume is a Novel Parameter when Assessing Symptom Burden from Liver Cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Avoiding both the surgically and oncologically futile use of ALPPS

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel two-stage hepatectomy that induces rapid growth of the remnant liver in primarily unresectable liver tumors by combining transection of the liver with portal vein ligation (1). Although the clinical outcomes demonstrated in the paper by Schnitzbauer et al . were very impressive and all the patients were able to proceed to a right trisectionectomy very shortly after the first procedure, the morbidity rate (64%) and the in-hospital mortality rate (12%) were incredibly high (1). Recently, an international registry system for this procedure has been created. This registry will gather important clinical data and can be used as a basis for establishing adequate patient selection and for improving the safety of this procedure.

Genome-wide random regression analysis for parent-of-origin effects of body composition allometries in mouse

Genomic imprinting underlying growth and development traits has been recognized, with a focus on the form of absolute or pure growth. However, little is known about the effect of genomic imprinting on relative growth. In this study, we proposed a random regression model to estimate genome-wide imprinting effects on the relative growth of multiple tissues and organs to body weight in mice. Joint static allometry scaling equation as sub-model is nested within the genetic effects of markers and polygenic effects caused by a pedigree. Both chromosome-wide and genome-wide statistical tests were conducted to identify imprinted quantitative trait nucleotides (QTNs) associated with relative growth of individual tissues and organs to body weight. Real data analysis showed that three of six analysed tissues and organs are significantly associated with body weight in terms of phenotypic relative growth. At the chromosome-wide level, a total 122 QTNs were associated with allometries of kidney, spleen and liver weights to body weight, 36 of which were imprinted with different imprinting fashions. Further, only two imprinted QTNs responsible for relative growth of spleen and liver were verified by genome-wide test. Our approach provides a general framework for statistical inference of genomic imprinting underlying allometry scaling in animals.

Weight–length relationships, weight conversion factors and somatic indices from two stocks of black anglerfish (Lophius budegassa) and white anglerfish (L. piscatorius) in north-eastern Atlantic waters

Weight–length relationships, weight conversion factors and somatic indices are presented from a decade (2006 to 2015) for two stocks of Lophius budegassa and L.piscatorius in northern Iberian Atlantic waters (ICES Div. VIIIc–IXa2) and in Celtic Sea, south-western Ireland and Porcupine Bank (Div. VIIb,c,h,j,k). A total of 3298 L.budegassa and 7219 L.piscatorius were sampled from commercial landings and research surveys. Total length (Lt), total weight (Wt), “commercial” weight (Wgl) and “scientific” weight (Wg) were obtained. The parameters (a, b) in the power relationships weight–length for combined sexes in L.budegassa were: 0.020, 2.916; 0.017, 2.929; 0.017, 2.922 for Wt, Wgl and Wg respectively in Div. VIIIc–IXa2; 0.025, 2.841; 0.013, 2.984; 0.013, 2.971 in Div. VIIb,c,h,j,k. For L.piscatorius: 0.025, 2.853; 0.020, 2.868; 0.024, 2.861 in Div. VIIIc–IXa2; 0.027, 2.826; 0.023, 2.825; 0.023, 2.816 in Div. VIIb,c,h,j,k. Significant differences between stocks were found in both species. The conversion factors between total and gutted weight in L.budegassa were: 1.186, 1.236 for Wgl and Wg respectively in Div. VIIIc–IXa2; 1.187, 1.233 in Div. VIIb,c,h,j,k. For L.piscatorius: 1.181, 1.241 in Div. VIIIc–IXa2; 1.210, 1.262 in Div. VIIb,c,h,j,k. The parameters can be used in the process of annual assessment of the state of each stock. Gonadosomatic index (GSI), hepatosomatic index (HSI) and Le Cren’s condition factor, indicators of reproductive and nutritional status, were seasonally analyzed and compared between sexes and stocks. Significant better condition and higher GSI and HSI were found in females. In Div. VIIb,c,h,j,k better condition was found for both species and higher GSI for L.piscatorius. The analysis throughout the year of GSI and HSI for L.budegassa showed seasonality in liver growth previous to spawn and corroborated the spawning season from January to June in VIIIc–IXa2. The parameters obtained were compared with previous ones from these and others Lophiiformes, showing common patterns.

한방차 조성물의 세포활성과 혈관이완 효과에 대한 융합적 연구

본 연구는 혈관 활성에 도움이 되는 한방차를 개발하고, 섭취효능에 대한 동 서 융합적인 접근 필요성에 대한 기초자료로 사용하고자 하였다. 이에 따라 기미론에 따라 혈관 활성을 가질 수 있는 포공영(Taraxaci Herba), 치자(Gardeniae Fructus), 감국(Chrysanthemum indicum) 및 금은화(Lonicerae Flos)를 선정하여 조성물을 만들고 각각 재료와 조성물의 영양성분, 조성물이 세포활성에 미치는 영향 및 수축혈관에 대한 이완정도를 분석하였다. 기미론적 원리에 따른 한방차 조성물은 체내 열을 제거하고 혈액순환을 촉진할 수 있는 효능을 가지고 있음을 알 수 있었다. 네 가지를 재료를 배합한 조성물은 세포활성에 유익한 영향을 미치고 있음을 확인하였다. 또한 조성물은 수축혈관에 대해 이완효과를 가지고 있었고 조성물의 농도가 높을수록 수축된 혈관의 이완효과가 큰 것으로 관찰되어 이 조성물이 혈관 활성에 긍정적 영향을 주고 있음을 확인하였다. 본 연구는 한방차 조성물의 기미 특성과 현대 영양학의 특성이 융합된 섭취효능을 제시하였다고 사료된다. This study was aimed to secure the basis for developing the hangbang-tea may help promote healthy blood vessels by natural herbal ingredients formulated in accordance with the basic principles of oriental medicinal theory. We investigated the vessels contracted by concentrations and safety assessment carried out by the cell viability of Taraxaci Herba, Gardeniae Fructus, Chrysanthemum indicum and Lonicerae Flos composition and concentration. We found cell survival were higher than the control group show a beneficial trend in the growth of normal liver and kidney cells. As a results of this study will be the basis to develop the hangbang-tea differentiated in the future oriental medicine resources. Medicinal resources will be hangbang-tea based on clinical trials utilizing herbal western and oriental medicine convergence principle and vascular relaxation mechanism.

A metabolomic approach shows sphingosine 1-phosphate and lysophospholipids as mediators of the therapeutic effect of liver growth factor in emphysema

Tobacco smoke exposure is the principal cause of lung tissue destruction, which in turn results in emphysema that leads into shortness of breath. Liver growth factor (LGF, a cell and tissue regenerating factor with therapeutic activity in several organs) has antifibrotic and antioxidant properties that could be useful to promote lung tissue regenerating capacity in damaged lungs. The current study has examined differences in metabolite profiles (fingerprints) of plasma from mice (strain C57BL/6J, susceptible to develop emphysema) exposed to tobacco smoke during six months. One group of mice received a treatment with Liver Growth Factor (LGF) after emphysema was established, whereas the other group did not receive the treatment. Age and sex-matched mice not exposed to smoke were also maintained with or without treatment as controls. Metabolic fingerprints (untargeted analysis) of plasma after protein precipitation were obtained by LC-QTOF-MS. The signals were processed and a large number of possible metabolites were found (23944). Multivariate data analysis provided models that highlighted the differences between control and smoke exposed mice in both conditions. Accurate masses of features (possible compounds) representing significant differences were searched using online public databases. Lipid mediators, related to intracellular signaling in inflammation, were found among the metabolites putatively identified as markers of the different conditions and among them, sphingosine, sphingosine 1-phosphate and lysophospholipids point at the relevance of such metabolites in the regulation of the processes related to tissue regeneration mediated by LGF. These results also suggest that metabolomic fingerprinting could potentially guide the characterization of relevant metabolites leading the regeneration of lungs in emphysema disease.

Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model

The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic acid, OCA) on liver growth following portal vein embolization (PVE). Rabbits were allocated to receive daily oral gavage with OCA (10 mg/kg) or vehicle (control group) starting 7 days before PVE (n = 18 per group), and continued until 7 days after PVE. PVE of the cranial liver lobes was performed using polyvinyl alcohol particles and coils on day 0. Caudal liver volume (CLV) was analysed by CT volumetry on days -7, -1, +3 and +7. Liver function was determined by measuring mebrofenin uptake using hepatobiliary scintigraphy. Additional parameters analysed were plasma aminotransferase levels, and histological scoring of haematoxylin and eosin- and Ki-67-stained liver sections. Three days after PVE of the cranial lobes, the increase in CLV was 2·2-fold greater in the OCA group than in controls (mean(s.d.) 56·1(20·3) versus 26·1(15·4) per cent respectively; P < 0·001). This increase remained greater 7 days after PVE (+1·5-fold; P = 0·020). The increase in caudal liver function at day +3 was greater in OCA-treated animals (+1·2-fold; P = 0·017). The number of Ki-67-positive hepatocytes was 1·6-fold higher in OCA-treated animals 3 days after PVE (P = 0·045). Plasma aminotransferase levels and histology did not differ significantly between groups. OCA accelerated liver regeneration after PVE in a rabbit model. OCA treatment might increase the efficacy of PVE and, thereby, resectability. Surgical relevance Liver failure is the most feared complication after liver surgery, with no effective treatment options. Liver regeneration is essential to avoid liver failure, and recently bile acid signalling was implicated in the initiation of liver regeneration through the nuclear bile acid receptor farnesoid X receptor (FXR). In this study, the potent FXR agonist obeticholic acid accelerated liver regeneration following portal vein embolization in a rabbit model, in terms of liver volume, liver function and proliferation. Obeticholic acid treatment could enhance the efficacy of portal vein embolization, thereby increasing resectability, and could reduce the interval to surgery. In addition, obeticholic acid might have a place in the prevention of liver failure after liver surgery.

Hepatic parenchymal transection increases liver volume but not function after portal vein embolization in rabbits

Associating liver partition with portal vein ligation for staged hepatectomy induces more extensive liver hypertrophy than ligation alone; however, the mechanisms underlying the accelerated liver regrowth and the functional quality of the hypertrophic liver are presently elusive. This study, therefore, investigated the effect of parenchymal transection on liver volume and function after portal vein embolization in a standardized rabbit model. Twelve rabbits were subjected to portal vein embolization of the cranial liver lobes and randomized between parenchymal transection of the left lateral liver lobe versus no transection (portal vein embolization only). Liver volume of the nonembolized liver lobe was assessed using computed tomography-volumetry, and liver uptake function was determined by 99mTc-mebrofenin hepatobiliary scintigraphy before and 3 and 7days after portal vein embolization. The increase in nonembolized liver volume 3days after portal vein embolization was 2.7-fold greater in the transected group compared with the portal vein embolization only group (56 ±16% vs 21 ±12%, respectively, P<.01) and 1.7-fold greater 7days after portal vein embolization (113 ±34% vs 68 ±24%, P<.01). Liver uptake function did not differ between groups before portal vein embolization (8.4 ±3.7%/min in the transection group vs 8.9 ±1.6%/min) on day 3 (33.2 ±4.7% after transection vs 30.3 ±4.6%/min, respectively) and day 7 after portal vein embolization (42.6 ±8.4% vs 39.1 ±5.3%/min, respectively). Parenchymal transection after portal vein embolization increases liver growth in terms of volume but not function. These results indicate that the rapid volume increase observed after associating liver partition with portal vein ligation for staged hepatectomy does not coincide with the clinically more relevant functional increase. Quantitative liver function tests might be essential in associating liver partition with portal vein ligation for staged hepatectomy to better assess the hypertrophy response and improve clinical decision-making.

Effects of Metreleptin in Pediatric Patients With Lipodystrophy.

Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Prospective, single-arm, open-label studies with continuous enrollment since 2000. National Institutes of Health, Bethesda, Maryland. Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia). Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d). Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment. After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty. Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Peroxisome proliferator-activated receptor γ activation inhibits liver growth through miR-122-mediated downregulation of cMyc

Although NR1C3 agonists inhibit cell growth, the molecular mechanism of their action has not been thoroughly characterized to date. A recent study demonstrated that NR1C3 can regulate miR-122 by binding to its promoter. Given that miR-122 can indirectly regulate cMyc-mediated promitogenic signaling by targeting E2f1, we hypothesized that NR1C3 activation inhibits hepatocyte proliferation through miR-122-mediated cMyc downregulation. In the present study, we examined if liver hyperplasia induced by a strong chemical mitogen for the liver, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of NR1I3, can be repressed by NR1C3 activation through miR-122 upregulation. Acute TCPOBOP treatment caused a significant increase in liver-to-body weight ratio. The liver mass increase was accompanied with miR-122 downregulation. ChIP assays demonstrated that TCPOBOP-activated NR1I3 accumulated on the DR1 site in the pri-miR-122 promoter; and the NR1I3 accumulation is accompanied by a decrease in miR-122 and an increase in E2f1 and its transcription target cMyc. Rosiglitazone (Ros) treatment, which is an agonist of NR1C3, caused an opposite effect on liver-to-body weight ratio. When Ros was given with TCPOBOP, it attenuated the inhibitory effect of TCPOBOP on miR-122. Moreover, Ros treatment inhibited the NR1I3 binding with the DR1 site in the pri-miR-122 promoter. Furthermore, the increase of miR-122 produced by Ros was correlated with the downregulation of its targets, E2f1 and cMyc. Thus, our finding demonstrated that the liver growth inhibitory effect of NR1C3 activation was at least partly related to the decrease of cMyc though the activation of miR-122 and the downregulation of E2f1.

High dietary energy level stimulates growth hormone receptor and feed utilization in large Atlantic salmon (Salmo salarL.) under hypoxic conditions

This study examines how appetite and growth regulation of Atlantic salmon are affected by low dissolved oxygen (LO) and dietary digestible energy levels (DE: high [HE] vs. low [LE]). Long-term exposure to LO resulted in a reduced feed intake, growth, digestible protein and fat retention efficiencies and increased feed conversation ratio and plasma ghrelin concentrations (p < .05) compared to high dissolved oxygen (HO). Pair-feeding of rations based on the feed intake of the LO groups, but fed at HO, resulted in a 50% growth improvement in HE diet groups. This suggests that the poor growth under LO was not entirely caused by the reduced feed intake. Salmon adapted to LO by increased haemoglobin concentrations, while osmoregulation was affected by increased plasma chloride concentrations (p < .05). Plasma ghrelin concentration was unaffected by DE (p > .05). Growth regulation was affected by the HE diet, with increased liver and muscle growth hormone receptor ghr1 mRNA (p < .05), regardless of oxygen level. The growth depression due to low oxygen appears to be related to higher metabolic costs, while higher DE upregulates the GH-IGF system at the ghr1 level and found to be beneficial for growth, feed intake, oxyregulation and osmoregulation under hypoxia.