Peroxisome Proliferator-activated Receptor-gamma Coactivator-1beta Research Articles

Characterizing MetALD in a Nonhuman Primate Model using High Fat and Sucrose Diet and Chronic Binge Alcohol Administration

Mechanisms leading to metabolic and alcohol associated liver disease (MetALD) are not clearly delineated. This study examined the differential regulation of markers of hepatic mitochondrial function in nonhuman primates fed a high fat/high sucrose (HFSD) and administered chronic binge alcohol (CBA) or vehicle as compared to control-fed animals. We hypothesized that markers of hepatic dysregulation due to HFSD will be further altered by the combination of CBA/HFSD. Eight rhesus macaques were fed HFSD (27% sucrose and 42% fat, by kcal) with n=4 receiving vehicle and n=4 receiving 13-14g/kg/wk of ethanol through a gastric catheter. Rhesus macaques fed standard primate chow were used as reference controls (n=4-6). Liver RNA was isolated for determining expression of genes regulating mitochondrial biogenesis and function using RT-qPCR. Results were analyzed using one-way ANOVA and post-hoc pairwise multiple comparisons were performed using Tukey’s method, with alpha set to 0.05. Expression of inflammatory genes was significantly altered across the groups (p<0.05). HFSD increased tumor necrosis factor alpha (p=0.01), interleukin 1-beta (p=0.04), cluster of differentiation 38 (p=0.01), and transforming growth factor beta (p=0.01) expression compared to control. Both HFSD and CBA/HFSD increased interleukin-10 compared to control (p=0.02, p=0.03). Gene expression of mitochondrial function and oxidative stress regulators were significantly altered across the groups (p<0.05). CBA/HFSD decreased expression of peroxisome proliferator-activated receptor-gamma coactivator-1 beta (p=0.04) and nuclear respiratory factor 2 (p=0.04) compared to control. Both HFSD and CBA/HFSD decreased peroxisome proliferator-activated receptor alpha expression compared to control (p=0.01, 0.01). HFSD decreased superoxide dismutase 2 (SOD2) expression compared to control (p=0.01) and increased uncoupling protein 2 (p=0.01). SOD2 expression was increased only in CBA/HFSD compared to HFSD (p=0.01). These results reveal marked HFSD-mediated increases in markers of inflammation and CBA/HFSD-mediated changes in markers of mitochondrial function regulation and oxidative stress regulation. These findings suggest a greater impact of calorie-dense diets than CBA on hepatic inflammation and a combined impact of CBA and HFSD on mitochondrial regulation. Ongoing studies will examine oxidative phosphorylation complex protein activities and expression to elucidate and integrate HFSD or CBA mediated changes in hepatic bioenergetic capacity. Supported by F30AA030910, P60AA009803, and T32AA007577. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MiR-2382-5p Regulates Lipid Metabolism by Targeting NDRG2 in Mammary Epithelial Cells of Dairy Cattle.

microRNA is a class of single-stranded RNA molecules of about 22-24 nucleotides in length, which regulate a variety of biological processes, including lipid metabolism and triglyceride synthesis at transcriptional and translational levels by degrading target mRNAs or interfering with the protein production. In this study, the effect of miR-2382-5p on triglyceride levels was examined in bovine mammary epithelial cells (BMECs), and the results showed that miR-2382-5p could decrease the content of triglyceride. Furthermore, miR-2382-5p regulated the expression of lipoprotein lipase (LPL), peroxisome proliferator-activated receptor gamma co-activator 1beta (PPARGC1B), hormone-sensitive lipase (HSL), and peroxisome proliferator-activated receptor gamma (PPARγ), which are known to increase triglyceride decomposition in lipid metabolism. Luciferase reporter assay and quantitative real-time PCR (qPCR) validated that miR-2382-5p downregulated the mRNA expression of target gene N-myc downstream-regulated gene 2 (NDRG2) by specifically recognizing and binding to its 3'-untranslated region (UTR). Meanwhile, overexpression of NDRG2 led to increased triglyceride and cholesterol production in BMECs. In summary, this study suggested that miR-2382-5p regulated lipid metabolism by targeting NDRG2, which might be a potential target for molecular manipulation of milk fat composition to produce healthy milk. This study also provided basic data for further understanding lipid metabolism in dairy cattle.

Potential mechanism of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta on promoting osteoclastogenesis

Objective: To investigate the role of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1β) on osteoclastogenesis and related regulatory mechanism in the mouse monocyte-macrophage cell line (RAW264.7). Methods: PGC-1β expression and location in RAW264.7 cells was detected by immunofluorescence, flow cytometry and western blot analysis with nuclear protein extraction. RAW264.7 cells were transfected with lentivirus for gene silencing or over-expression of PGC-1β and cultured with macrophage colony-stimulating factor and receptor activator for nuclear factor-κB ligand. Cell viability was detected by cell counting kit-8. Cell apoptosis and cell cycle were detected by flow cytometry. Mature osteoclasts and their bone resorption activity were determined by tartrate-resistant acid phosphatase (TRAP) expression and toluidine blue staining. Western blot analysis was performed for detecting dendritic cell-specific transmembrane protein (DC-STAMP), cathepsin K, TRAP and matrix metalloproteinase (MMP)-9 expression, as well as cytoplasmic NF-κB-inducing kinase (NIK) and nuclear RelB. Results: PGC-1β expression was observed in the nuclei of RAW264.7 cells. Down-regulation or overexpression of PGC-1β in RAW264.7 cells did not affect cell viability, apoptosis or cell cycle. Down-regulation of PGC-1β decreased the count of mature osteoclasts (49±21 cells vs. 147±42 cells, P=0.004) and the pit area of bone resorption lacunae (42.11μm(2)±11.30 μm(2) vs. 204.80μm(2)±31.09 μm(2), P<0.001), as well as the expression of cathepsin K, TRAP and MMP-9, but not DC-STAMP. Overexpression of PGC-1β promoted osteoclast differentiation and bone resorption activity, as well as the expression of cathepsin K, TRAP and MMP-9. Down-regulation of PGC-1β suppressed the protein expression of cytoplasmic NIK and nuclear RelB in RAW264.7 cells. Conclusion: PGC-1β can promote the differentiation of RAW264.7 into osteoclasts and improve the bone resorption ability of the cells via activation of NIK/RelB pathway, which might be a promising therapeutic target for osteoporosis.

Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis.

Aplastic anaemia (AA) is a life‐threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM‐derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM‐MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM‐MSCs through lentivirus‐mediated ZFP36L1 knock‐down and overexpression assay. Peroxisome proliferator‐activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3′‐untranslated region bears adenine‐uridine‐rich elements was verified as a direct downstream target of ZFP36L1, and knock‐down of PPARGC1B impaired the adipogenesis of AA BM‐MSCs. Collectively, our work demonstrated that ZFP36L1‐mediated post‐transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM‐MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.

Regulation of CBL and ESR1 expression by microRNA-22‑3p, 513a-5p and 625-5p may impact the pathogenesis of dust mite-induced pediatric asthma.

Despite evidence for the involvement of microRNAs (miRNAs or miRs) in pediatric asthma, the mechanism responsible has not yet been fully elucidated. We aimed to identify novel miRNAs and to study their pathogenic role(s) in children with dust mite-induced asthma in order to gain a better understanding of the underlying mechanism responsible for this disease. For this purpose, 62 patients with asthma as well as 62 age- and gender-matched healthy controls were recruited. Twelve pairs of subjects were randomly subjected to microarray-based discovery analysis using a miRCURY LNA™ array. The differential expression of miRNAs and their targeted messenger RNAs were validated using RT-qPCR. Plasma concentrations of cytokines were determined using an enzyme-linked immunosorbent assay (ELISA) kit. The results revealed that three novel miRNAs - miR-22-3p, miR-513a-5p and miR-625-5p - were significantly downregulated in the asthma group compared with the control group (p<0.01), whereas the transcript levels of Cbl proto-oncogene, E3 ubiquitin protein ligase (CBL), peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), and estrogen receptor 1 (ESR1) that are targeted by these miRNAs were increased (p<0.01). There were significant differences in the plasma concentrations of γ-interferon, tumor necrosis factor-α, interleukin (IL)-12 and IL-10 between the two groups (p<0.05). Thus, miR-513a-5p, miR-22-3p and miR-625-5p may have an impact on the regulation of the immune response and inflammatory cytokine pathways through the regulation of their target gene(s), CBL, PPARGC1B and ESR1, which may then lead to a dust mite-induced asthma attack. Our findings may provide novel insights into the pathogenesis of pediatric asthma.

Functional Characterization of Exonic Variants of the PPARGC1B Gene in Coregulation of Estrogen Receptor Alpha.

Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a coactivator of estrogen receptor (ER)α and ERβ. We previously demonstrated a significant association between a variant of exon 5 of the PPARGC1B gene (+102525 G>A, R265Q) and airway hyperreactivity (AHR). The aims of the study were to evaluate the genetic effects of variants of the PPARGC1B gene on the function of ERs. PPARGC1B +102525G and A gene constructs were generated using PCR and cloned into a pCMV4 promoter vector. A luciferase reporter assay was undertaken in 293T cells cotransfected with one of the PPARGC1B +102525G>A constructs, ERα, and an estrogen response element (ERE) containing a luciferase construct after treatment with 17β-estradiol. According to the luciferase reporter assay, the +102525A allele showed higher ERα activity than the +102525G allele in response to stimulation with 17β-estradiol. In addition, the interaction between ERα and PPARGC1B was evaluated by coprecipitation assay. Human influenza hemagglutinin-tagged PPARGC1B coprecipitated more intensely with ERα in the +102525A than the +102525G construct after 17β estradiol treatment. The variant +102525A allele enhances the activity of ERα to a greater degree than the +102525G allele of PPARGC1B.

Novel Polymorphisms of Adrenergic, Alpha-1B-, Receptor and Peroxisome Proliferator-activated Receptor Gamma, Coactivator 1 Beta Genes and Their Association with Egg Production Traits in Local Chinese Dagu Hens.

Adrenergic, alpha-1B-, receptor (ADRA1B) and peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B) genes are involved in regulation of hen ovarian development. In this study, these two genes were investigated as possible molecular markers associated with hen-housed egg production, egg weight (EW) and body weight in Chinese Dagu hens. Samples were analyzed using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique, followed by sequencing analysis. Two novel single nucleotide polymorphisms (SNPs) were identified within the candidate genes. Among them, an A/G transition at base position 1915 in exon 2 of ADRA1B gene and a T/C mutation at base position 6146 in the 3′-untranslated region (UTR) of PPARGC1B gene were found to be polymorphic and named SNP A1915G and T6146C, respectively. The SNP A1915G (ADRA1B) leads to a non-synonymous substitution (aspartic acid 489-to-glycine). The 360 birds from the Dagu population were divided into genotypes AA and AG, allele A was found to be present at a higher frequency. Furthermore, the AG genotype correlated with significantly higher hen-housed egg production (HHEP) at 30, 43, 57, and 66 wks of age and with a higher EW at 30 and 43 wks (p<0.05). For the SNP T6146C (PPARGC1B), the hens were typed into TT and TC genotypes, with the T allele shown to be dominant. The TC genotype was also markedly correlated with higher HHEP at 57 and 66 wks of age and EW at 30 and 43 wks (p<0.05). Moreover, four haplotypes were reconstructed based on these two SNPs, with the AGTC haplotype found to be associated with the highest HHEP at 30 to 66 wks of age and with higher EW at 30 and 43 wks (p<0.05). Collectively, the two SNPs identified in this study might be used as potential genetic molecular markers favorable in the improvement of egg productivity in chicken breeding.

Analysis of clinical indexes and RUNX3, TBKBP1, PPARGC1B polymorphisms in Chinese Han patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a genetically determined disease. Runt-related transcription factor 3 (RUNX3), tumor necrosis factor family member-associated NF-κB activator binding kinase 1 binding protein (TBKBP1), and peroxisome proliferator-activated receptor-gamma coactivator 1 beta (PPARGC1B) have recently been found to be associated with susceptibility to AS in patients of Western European descent. We hypothesize that these three genes may be related to clinical outcomes of Chinese Han AS patients. Blood samples were drawn from 396 HLA-B27-positive Chinese Han AS patients. Clinical indexes were scored for each patient, including the Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), which measure patients' function of daily life and severity of AS. Twelve tagSNPs were selected from these three genes and genotyped. We analyzed the clinical indexes in different genotyped patients to investigate the relationship between severity of AS and different genotypes. The rs11249215 SNP in RUNX3 and the rs7379457 and rs32579 SNPs in PPARGC1B significantly affect the BASFI score in patients. The rs11249215, rs7551188, and rs1395621 SNPs in RUNX3 significantly affect the BASDAI scores. The two selected single nucleotide polymorphisms (SNPs) in TBKBP1 show no relationship with the clinical outcomes. None of the 12 SNPs is related to mSASSS. In conclusion, RUNX3 is related to both the severity of AS and the function of daily life. PPARGC1B is related to the function of daily life.

Genetic variants associated with sleep disorders

ObjectiveThe diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. MethodsPatients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. ResultsIn peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. ConclusionsSNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

Down-regulating peroxisome proliferator-activated receptor-gamma coactivator-1 beta alleviates the proinflammatory effect of rheumatoid arthritis fibroblast-like synoviocytes through inhibiting extracellular signal-regulated kinase, p38 and nuclear factor-kappaB activation.

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1β) is a transcriptional coactivator that plays important roles in regulating multiple aspects of energy metabolism and cytokine signaling pathways. PGC-1β overexpression leads to the attenuation of macrophage-mediated inflammation. In this study, we aimed to determine the expression of PGC-1β in RA synovium and fibroblast-like synoviocytes (FLS), and explore the mechanisms of PGC-1β on both the proinflammatory effects and apoptosis in RA-FLS.MethodsSynovium was obtained from 31 patients with active RA, as well as 13 osteoarthritis (OA) and 10 orthopedic arthropathies (Orth.A) as “less inflamed” disease controls. FLS were then isolated and cultured. Synovial PGC-1β expression was determined by immunohistochemistry staining, while FLS PGC-1β expression was detected by immunofluorescence staining, quantitative real-time PCR (qPCR) assay and western blot. PGC-1β was depleted by lentivirus sh-RNA, and up-regulated by pcDNA3.1- PGC-1β. The expression of proinflammatory cytokines, matrix metalloproteinases and receptor activator of nuclear factor-kappaB ligand was analyzed by qPCR, cytometric bead array and western blot. The expression of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) was determined by qPCR and western blot. Besides, cell apoptosis was examined using flow cytometry. The interaction between PGC-1β and NF-κB was performed by dual-luciferase reporter gene assays.Results(A) Synovial PGC-1β was over-expressed in RA patients compared with OA or Orth.A patients. (B) PGC-1β expression significantly increased in RA-FLS compared with OA-FLS. (C) PGC-1β mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-κB in RA-FLS. (D) PGC-1β mediated NF-κB transcription in RA-FLS, but did not affect ERK and p38.ConclusionThe results indicate that PGC-1β may play important roles in the proinflammatory effects and apoptosis of RA-FLS.

Genetic effect of single‐nucleotide polymorphisms in the PPARGC1B gene on airway hyperreactivity in asthmatic patients

Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a co-activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development. Genetic association of single-nucleotide polymorphisms (SNPs) in the PPARGC1B gene with the risk of asthma and airway hyperreactivity (AHR) was investigated, as well as the functional effects of these SNPs on PPARGC1B gene and protein expression. Direct sequencing of DNA from 24 Korean was performed to identify PPARGC1B SNPs. Genotyping was done in 264 controls and 949 asthmatics using single-base extension methods. PPARGC1B mRNA levels were measured using real-time PCR methodology. Luciferase and electrophoretic mobility shift assays (EMSA) were performed to functionally analyse PPARGC1B SNPs on promoter. Eighteen SNPs and one insertion/deletion polymorphism were identified, and seven SNPs were genotyped. No significant difference existed in the distribution of SNPs and haplotypes between the asthmatics and controls. However, the allele frequency of -427C>T and +102525G>A;R265Q showed a significant association with log-transformed PC(20) methacholine values in the asthmatics (P=0.005-0.0004). Real-time PCR demonstrated higher PPARGC1B mRNA levels in asthmatics having -427CC allele than in those having -427TT or CT alleles (P=0.048). The ratio of the mRNA expression for each PPARGC1B exon4-mRNA compared with the wild type was similar in peripheral blood mononuclear cells carrying the +102525G>A allele. Luciferase reporter assays revealed that -427C allele caused higher promoter activity than -427T allele. EMSA demonstrated that -427C allele exhibited stronger binding activity to a nuclear protein in 293T cells than did the -427T allele. Polymorphisms of -427C>T on the promoter and those of +102525G>A on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. The PPARGC1B genotypes may serve as genetic markers for AHR.

Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis

Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we determined whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Incubating primary hepatocyte cultures with recombinant FGF-19 suppressed the ability of insulin to stimulate fatty acid synthesis. This effect was associated with a reduction in the expression of lipogenic enzymes. FGF-19 also suppressed the insulin-induced expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. FGF-19 inhibition of lipogenic enzyme expression was not mediated by alterations in the activity of the insulin signal transduction pathway or changes in the activity of ERK, p38 MAPK, and AMP-activated protein kinase (AMPK). In contrast, FGF-19 increased the activity of STAT3, an inhibitor of SREBP-1c expression and decreased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), an activator of SREBP-1c activity. FGF-19 also increased the expression of small heterodimer partner (SHP), a transcriptional repressor that inhibits lipogenic enzyme expression via a SREBP-1c-independent mechanism. Inhibition of SREBP-1c activity by changes in STAT3 and PGC-1beta activity and inhibition of gene transcription by an elevation in SHP expression can explain the inhibition of lipogenesis caused by FGF-19. In summary, the inhibitory effect of FGF-19 on insulin activation of hepatic fatty acid synthesis constitutes a mechanism that would explain the beneficial effect of FGF-19 on metabolic syndrome.

Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation

Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.

Aberrant Forkhead Box O1 Function Is Associated with Impaired Hepatic Metabolism

FoxO1 plays an important role in mediating the effect of insulin on hepatic metabolism. Increased FoxO1 activity is associated with reduced ability of insulin to regulate hepatic glucose production. However, the underlying mechanism and physiology remain unknown. We studied the effect of FoxO1 on the ability of insulin to regulate hepatic metabolism in normal vs. insulin-resistant liver under fed and fasting conditions. FoxO1 gain of function, as a result of adenovirus-mediated or transgenic expression, augmented hepatic gluconeogenesis, accompanied by decreased glycogen content and increased fat deposition in liver. Mice with excessive FoxO1 activity exhibited impaired glucose tolerance. Conversely, FoxO1 loss of function, caused by hepatic production of its dominant-negative variant, suppressed hepatic gluconeogenesis, resulting in enhanced glucose disposal and improved insulin sensitivity in db/db mice. FoxO1 expression becomes deregulated, culminating in increased nuclear localization and accounting for its increased transcription activity in livers of both high fat-induced obese mice and diabetic db/db mice. Increased FoxO1 activity resulted in up-regulation of hepatic peroxisome proliferator-activated receptor-gamma coactivator-1beta, fatty acid synthase, and acetyl CoA carboxylase expression, accounting for increased hepatic fat infiltration. These data indicate that hepatic FoxO1 deregulation impairs the ability of insulin to regulate hepatic metabolism, contributing to the development of hepatic steatosis and abnormal metabolism in diabetes.

Putative association of peroxisome proliferator‐activated receptor γ co‐activator 1β (PPARGC1B) polymorphism with Type 2 diabetes mellitus

Peroxisome proliferator-activated receptor gamma co-activator 1beta (PPARGC1B) may play an important role in obesity and Type 2 diabetes mellitus (T2DM). In an effort to identify genetic polymorphisms in potential candidate genes for T2DM, genetic associations of PPARGC1B were examined in a Korean T2DM study. We have sequenced the PPARGC1B, and examined its association with T2DM and diabetic phenotypes in a Korean T2DM study (775 T2DM patients and 316 control subjects) using the TaqMan method. Logistic and multiple regression models were employed to analyse the genetic contributions of polymorphisms. Nineteen polymorphisms were identified in PPARGC1B. By logistic regression analysis controlling for age and sex as covariates, one non-synonymous single-nucleotide polymorphism (SNP; +102605C>A; Arg292Ser) in exon 5 showed marginal significant associations with the risk of T2DM. The allele frequency of the minor allele ['A (= Ser)' allele of +102605C>A] was lower among T2DM patients (frequency = 0.101) than among control subjects (frequency = 0.135) [P = 0.03, OR = 0.71 (95% CI: 0.51-0.94)]. Furthermore, serum triglyceride level was also associated with this non-synonymous SNP (+102605C>A; Arg292Ser) in exon 5 among controls (P = 0.03 in the dominant analysing model). Serum triglyceride levels [1.46 +/- 0.70 (log-transformed value; 0.12 +/- 0.18)] were lower in individuals who carry one or two copies of minor alleles than among others [1.60 +/- 0.85 (log-transformed value; 0.16 +/- 0.21)]. The present study provides, for the first time, information about genetic polymorphisms in PPARGC1B and putative associations of one non-synonymous SNP with the risk of T2DM and serum triglyceride (TG) levels in the Korean population, although this result was not significant after correction for multiple testing.

Tu-P8:315 Peroxisome proliferator-activated receptor gamma coactivator-1beta hepatic overexpression in mice results in combined hyperlipidemia

Tu-P8:315 Peroxisome proliferator-activated receptor gamma coactivator-1beta hepatic overexpression in mice results in combined hyperlipidemia