Hepatic Glucose Homeostasis Research Articles

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis

Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.

1,2-Dichloroethane impairs glucose and lipid homeostasis in the livers of NIH Swiss mice.

Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m3 of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m3 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m3 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m3 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.

Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD.

The rough fur (ruf) mutation in mice is an allele of myelin protein zero-like 3 (Mpzl3)

Background: The recessive rough fur mutation ( ruf )―named for the unkempt, greasy appearance of the hair coat in homozygotes―has previously been mapped on mouse Chromosome 9. However, the assignment of ruf to a particular gene is needed to facilitate a complete molecular analysis of the mutant phenotype. Results: To establish a more refined location for ruf (as a basis for positional cloning) DNA isolated from a large backcross family was typed for microsatellite and single-nucleotide markers on Chromosome 9. This analysis restricted the location of ruf between sites that flank only four genes known to be expressed in skin, one of which― Mpzl3 , for myelin protein zero-like 3―generates a similar hair phenotype in mice homozygous for engineered and spontaneous null-alleles. A cross between ruf mutants and mice heterozygous for the Mpzl3 rc mutation (which controls a recessive phenotype called rough coat) produced offspring that displayed matted, damp-looking fur, indicating that ruf is a mutant allele of Mpzl3 . However, sequence analysis of the Mpzl3 promoter, exons and splice junctions revealed no mutant-specific DNA defect. Conclusion: The results presented indicate that ruf is a mutant allele of Mpzl3 . With a genetic assignment in hand, the rough fur variant can now be more fully characterized to advance our understanding of Mpzl3 ’s role in normal skin development and function, hepatic triglyceride synthesis, weight regulation, energy and glucose homeostasis; and to model-related human disorders.

PNPLA3 rs1010023 Predisposes Chronic Hepatitis B to Hepatic Steatosis but Improves Insulin Resistance and Glucose Metabolism.

PNPLA3 polymorphisms serve as the genetic basis of hepatic steatosis in normal population and lead to dysregulated glucose metabolism. Whether it underlies the hepatic steatosis and glucose homeostasis in chronic hepatitis B patients remains uncertain. Here, we investigated the PNPLA3 polymorphisms in biopsy-proven chronic hepatitis B patients with (CHB+HS group, n = 52) or without hepatic steatosis (CHB group, n = 47) and non-CHB subjects with (HS group, n = 37) or without hepatic steatosis (normal group, n = 45). When compared to the TT genotype, C-allele at PNPLA3 rs1010023 (CC and TC genotypes) conferred higher risk to hepatic steatosis in chronic hepatitis B patients (odds ratio (OR) = 1.768, 95% confidence interval (CI): 1.027–3.105; P = 0.045) independent of age, gender, and body mass index. In contrast to their role in hepatic steatosis, CC and TC genotypes of PNPLA3 rs1010023 were correlated to significant improvement of homeostasis model assessment index (HOMA-IR) as compared to TT genotype in the CHB+HS group. Downregulated fasting blood glucose also characterized the CHB+HS patients with C-allele at PNPLA3 rs1010023 (CC/TC versus TT: 4.81 ± 0.92 mmol/L versus 5.86 ± 2.11 mmol/L, P = 0.02). These findings suggest that PNPLA3 rs1010023 may predispose chronic hepatitis B patients to hepatic steatosis but protects them from glucose dysregulation by attenuating insulin resistance.

Cichoric acid regulates the hepatic glucose homeostasis via AMPK pathway and activates the antioxidant response in high glucose-induced hepatocyte injury

CA regulates hepatic glucose homeostasisviathe AMPK pathway and improves hepatocyte injuryviaantioxidant responsein vitroandin vivo.

Combined Therapy With Swimming Exercise and a Diet Supplemented With Diphenyl Diselenide Is Effective Against Age-Related Changes in the Hepatic Metabolism of Rats.

Aging is characterized by a widespread loss of homeostasis in biological systems and is accompanied by pathophysiological changes including the liver injury. The aim of the present study was to investigate the effects of the combined therapy with swimming exercise (20 min session, 5 days/week during 4 weeks) and a diet supplemented with 1 ppm of (PhSe)2 on the hepatic metabolic alterations caused by aging in rats. In this study, male old Wistar rats had an increase in the epididymal fat relative weight, disturbances in the activities of hepatic enzymes associated to the glucose homeostasis, higher hepatic triglyceride content and higher activity of the plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The combined therapy normalized the activities of glucose-6-Pase and tyrosine aminotransferase, gluconeogenic enzymes, increased the hepatic glycogen content and was effective against the increase in the hepatic triglycerides content, without altering the activities of hexoquinase, and citrate synthase. Moreover, the combined therapy normalized the activities of AST and ALT, indicating a hepatoprotective effect. The combined therapy with swimming exercise and a diet supplemented with 1 ppm of (PhSe)2 contributed to the hepatic glucose homeostasis in old rats. Nevertheless, more studies are needed to investigate the possible mechanisms of action behind these effects. J. Cell. Biochem. 118: 1574-1582, 2017. © 2016 Wiley Periodicals, Inc.

Could post-weaning dietary chia seed mitigate the development of dyslipidemia, liver steatosis and altered glucose homeostasis in offspring exposed to a sucrose-rich diet from utero to adulthood?

The present work analyzes the effects of dietary chia seeds during postnatal life in offspring exposed to a sucrose-rich diet (SRD) from utero to adulthood. At weaning, chia seed (rich in α−linolenic acid) replaced corn oil (rich in linoleic acid) in the SRD. At 150 days of offspring life, anthropometrical parameters, blood pressure, plasma metabolites, hepatic lipid metabolism and glucose homeostasis were analyzed. Results showed that chia was able to prevent the development of hypertension, liver steatosis, hypertriglyceridemia and hypercholesterolemia. Normal triacylglycerol secretion and triacylglycerol clearance were accompanied by an improvement of de novo hepatic lipogenic and carnitine-palmitoyl transferase-1 enzymatic activities, associated with an accretion of n-3 polyunsaturated fatty acids in the total composition of liver homogenate. Glucose homeostasis and plasma free fatty acid levels were improved while visceral adiposity was slightly decreased. These results confirm that the incorporation of chia seed in the diet in postnatal life may provide a viable therapeutic option for preventing/mitigating adverse outcomes induced by an SRD from utero to adulthood.

Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus.

Clinical studies have revealed that testosterone supplementation had a positive effect on glucose homeostasis in type 2 diabetes mellitus (T2DM), but did not address how testosterone supplementation affected insulin responsiveness in the liver, a key glucose homeostatic organ. In this study, we aimed to study the effect of testosterone supplementation on hepatic insulin responsiveness and glucose homeostasis through liver in male high-fat diet-induced T2DM mice. Testosterone treatment to T2DM animals showed reduced hepatic glucose output. Testosterone inhibited the insulin signaling in liver, thus increased insulin resistance. However, testosterone treatment inactivated GSK3α independent of PI3K/AKT pathway and inhibited FOXO1 By interaction of androgen receptor to FOXO1 and downregulated PEPCK, causing repression of gluconeogenic pathway, which is otherwise upregulated in T2DM, resulted in better glucose homeostasis.

Abstract 12896: ApoC3-Gln38Lys Variant is a Gain-of-function Mutation Associated With Human Hypertriglyceridemia

Introduction: Cell culture and animal studies have suggested that expression of human apoC3 in liver cells can exert an intracellular role in promoting production of triglyceride (TG)-rich VLDL (VLDL1) under lipid-rich conditions. Previously, hypotriglyceridemia in human subjects have been linked to several loss-of-function apoC3 mutations, namely Ala23Thr and Lys58Glu. Conversely, hypertriglyceridemia has also been linked to an apoC3 variant. For example, the Gln38Lys variant was originally identified in human subjects of Mexican origin; heterozugous carriers of Gln38Lys exhibited moderate hypertriglyceridemia. Hypothesis: We hypothesized that the Gln38Lys variant is a gain-of-function mutation that promotes hepatic VLDL assembly/secretion. Methods: The recombinant Gln38Lys variant was either expressed in McA-RH7777 cells devoid of endogenous apoC3, or else expressed in apoc3-null mice using adenovirus-mediated gene transfer. The effect of Gln38Lys expression on hepatic lipogenesis, VLDL1 production, and glucose homeostasis was contrasted with that of wildtype apoC3. Results: Gln38Lys expression in McA-RH7777 cells and apoc3-null mice resulted in increased VLDL1-TG secretion, which was accompanied with increased de novo lipogenesis, increased adipogenesis, and severe hepatic steatosis (i.e. accumulation of TG and cholesteryl esters). Gln38Lys expression also increased glucose uptake and hepatic glycogen content, suggesting that apoC3 may play a role in hepatic glucose homeostasis. Live cell imaging revealed prominent association of apoC3 with endosomes, and the Gln38Lys-associated endosomes exhibited robust trafficking between Golgi apparatus and the cell periphery. Next generation sequencing of 1557 DNA samples from patients (of European, Chinese, African, and South Asian origins) with dyslipidemia (including hypertriglyceridemia, hypercholesterolemia and combined hyperlipidemia) did not detect Gln38Lys variant, nor was the Gln38Lys variant found in the ExAC databases containing 60,706 individuals. Conclusions: Gln38Lys is a rare, gain-of-function variant that may stimulate TG-rich VLDL1 production under lipid-rich conditions, contributing to hypertriglyceridemia..

Inflammation Improves Glucose Homeostasis through IKKβ-XBP1s Interaction

It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.

Donor Graft MicroRNAs: A Newly Identified Player in the Development of New-onset Diabetes After Liver Transplantation.

New‐onset diabetes after liver transplantation (NODALT) is a frequent complication with an unfavorable outcome. We previously demonstrated a crucial link between donor graft genetics and the risk of NODALT. We selected 15 matched pairs of NODALT and non‐NODALT liver recipients using propensity score matching analysis. The donor liver tissues were tested for the expression of 10 microRNAs (miRNAs) regulating human hepatic glucose homeostasis. The biological functions of potential target genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both miR‐103 and miR‐181a were significantly highly expressed in the NODALT group as compared to the non‐NODALT group. The predicted target genes (e.g. Irs2, Pik3r1, Akt2, and Gsk3b) were involved in glucose import and the insulin signaling pathway. We also observed dysregulation of miRNAs (e.g. let‐7, miR‐26b, miR‐145, and miR‐183) in cultured human hepatocytes treated with tacrolimus or high glucose, the two independent risk factors of NODALT identified in this cohort. The hepatic miRNA profiles altered by tacrolimus or hyperglycemia were associated with insulin resistance and glucose homeostatic imbalance as revealed by enrichment analysis. The disease susceptibility miRNA expressive pattern could be imported directly from the donor and consolidated by the transplant factors.

Hepatic Notch1 deletion predisposes to diabetes and steatosis via glucose-6-phosphatase and perilipin-5 upregulation

Notch signaling pathways have recently been implicated in the pathogenesis of metabolic diseases. However, the role of hepatic Notch signaling in glucose and lipid metabolism remains unclear and needs further investigation as it might be a candidate therapeutic target in metabolic diseases such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). We used hepatocyte-specific Notch1 knockout (KO) mice and liver biopsies from NASH and NAFLD patients to analyze the role of Notch1 in glucose and lipid metabolism. Hepatocyte-specific Notch1 KO mice were fed with a high fat diet (HFD) or a regular diet (RD). We assessed the metabolic phenotype, glucose and insulin tolerance tests, and liver histology. Hepatic mRNA expression was profiled by Affymetrix Mouse Gene arrays and validated by quantitative reverse transcription PCR (qPCR). Akt phosphorylation was visualized by immunoblotting. Gene expression was analyzed in liver biopsies from NASH, NAFLD, and control patients by qPCR. We found that Notch1 KO mice had elevated fasting glucose. Gene expression analysis showed an upregulation of glucose-6-phosphatase, involved in the final step of gluconeogenesis and glucose release from glycogenolysis, and perilipin-5, a regulator of hepatic lipid accumulation. When fed with an HFD KO mice developed overt diabetes and hepatic steatosis. Akt was highly phosphorylated in KO animals and the Foxo1 target gene expression was altered. Accordingly, a reduction in Notch1 and increase in glucose-6-phosphatase and perilipin-5 expression was observed in liver biopsies from NAFLD/NASH compared with controls. Notch1 is a regulator of hepatic glucose and lipid homeostasis. Hepatic impairment of Notch1 expression may be involved in the pathogenesis of human NAFLD/NASH.

MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis

MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes.

Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.

Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults.

TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.

To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy.

The role of mir-124 and aurora kinase A in the multidrug resistance in HCC

s / Digestive and Liver Disease 48S (2016) e1–e17 e9 We found that Ruvbl1+/− mice had reduced hepatocyte turnover and proliferation after partial hepatectomy, thus explaining the delay in the onset of cancer after DEN. Consistently, in vitro silencing of Ruvbl1 reduced the cell growth of both non-transformed (AML-12) and HCC cell lines (HepG2, Hepa1-6). Unexpectedly, Ruvbl1+/− mice showed higher blood glucose and insulin levels, reduced glucose tolerance, insulin-resistance, increased hepatic glucose output and reduced liver glycogen storage. Insulin-induced phosphorylation of Akt,mTOR and FOXOswas reduced in Ruvbl1+/− mice as well as in Ruvbl1-silenced AML-12 cells. 2D-DIGE proteomics analysis revealed a significant alteration of carboxylic-acids metabolism in Ruvbl1-silenced Hepa1-6 cells. Therefore, despite the initial delay in cancer appearance, the onset of insulin resistance likely promotesHCCprogression in thismodel. Taken together these results highlight a central role of Ruvbl1 in the maintenance of hepatic glucose homeostasis and insulinsensitivity through the Akt-mTOR pathway, and strongly suggest that deregulation of this pathway by Ruvbl1 over-expression is a key event in the oncogenic transformation and HCC progression. This research is founded by the ItalianMinistry of Health (Grant no:GR-2009-1600315) and Ente cassa di Risparmio di Firenze (Grant no: 2013.0673). http://dx.doi.org/10.1016/j.dld.2015.12.031

Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss.

ObjectiveObesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss.MethodsWe compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery.ResultsCompared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%).ConclusionsThese results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.

SAT-055 - Prognostic Relevance of Stage Migration in Patients with Hepatocellular Carcinoma: A Multicenter Cohort Study

s / Digestive and Liver Disease 48S (2016) e1–e17 e9 We found that Ruvbl1+/− mice had reduced hepatocyte turnover and proliferation after partial hepatectomy, thus explaining the delay in the onset of cancer after DEN. Consistently, in vitro silencing of Ruvbl1 reduced the cell growth of both non-transformed (AML-12) and HCC cell lines (HepG2, Hepa1-6). Unexpectedly, Ruvbl1+/− mice showed higher blood glucose and insulin levels, reduced glucose tolerance, insulin-resistance, increased hepatic glucose output and reduced liver glycogen storage. Insulin-induced phosphorylation of Akt,mTOR and FOXOswas reduced in Ruvbl1+/− mice as well as in Ruvbl1-silenced AML-12 cells. 2D-DIGE proteomics analysis revealed a significant alteration of carboxylic-acids metabolism in Ruvbl1-silenced Hepa1-6 cells. Therefore, despite the initial delay in cancer appearance, the onset of insulin resistance likely promotesHCCprogression in thismodel. Taken together these results highlight a central role of Ruvbl1 in the maintenance of hepatic glucose homeostasis and insulinsensitivity through the Akt-mTOR pathway, and strongly suggest that deregulation of this pathway by Ruvbl1 over-expression is a key event in the oncogenic transformation and HCC progression. This research is founded by the ItalianMinistry of Health (Grant no:GR-2009-1600315) and Ente cassa di Risparmio di Firenze (Grant no: 2013.0673). http://dx.doi.org/10.1016/j.dld.2015.12.031

Forkhead Box P1 (FOXP1) Transcription Factor Regulates Hepatic Glucose Homeostasis

Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.