Analysis of the mechanisms mediating the regulation of acetyl -CoA carboxylase transcription by the liver X receptor and chenodeoxycholic acid

Agonists of the liver X receptor (LXR) prevent and decrease arterial plaque formation in experimental models of atherosclerosis. The anti-atherosclerotic effects of LXR agonists are mediated by an increase in expression of genes involved in cholesterol export. Currently, the therapeutic utility of LXR agonists is limited by the fact that these agents increase triglyceride levels in the blood and liver. These undesired effects are caused by an increase in transcription of genes controlling triglyceride synthesis, such as acetyl CoA carboxylasealpha (ACCalpha). We have demonstrated that a synthetic LXR agonist, T0-901317 increases ACCalpha via both a direct mechanism involving the activation of LXR/retinoid X receptor (RXR) heterodimers on the ACCalpha gene and by an indirect mechanism involving the increased expression of sterol regulatory element binding protein-1 (SREBP-1). SREBP-1 binds a site adjacent to the ACCalpha LXRE and enhances the ability of LXR/RXR to activate ACCalpha transcription. We screened a number of compounds for their ability to inhibit the stimulatory effects of T0-901317 on expression of lipogenic genes in primary cultures of hepatocytes. We found that the bile acid, chenodeoxycholic acid (CDCA), inhibited the T0-901317-induced increase in mRNA abundance encoding ACCalpha, fatty acid synthase, and stearoyl CoA desaturase-1. CDCA also blocked the stimulatory effects of T0-901317 on triglyceride secretion into the culture medium. Results from transient transfection analyses identified two cis-acting elements that mediated the inhibitory effects of CDCA on T0-901317-induced ACCalpha transcription. One element bound LXR/RXR heterodimers and the other element bound SREBP-1. Treatment with CDCA decreased the expression of mature, active SREBP-1 and decreased the binding of LXR/RXR heterodimers to the ACCalpha promoter. Further studies demonstrated that the CDCA-mediated inhibition of ACCalpha transcription was associated with an activation of extracellular signal-related kinase-1/2 (ERK1/2) and p38 mitogen activated protein kinase (p38MAPK) and that inhibitors of ERK1/2 and p38MAPK abolished or substantially attenuated the inhibitory effect of CDCA on ACCalpha expression. These results indicate that CDCA inhibits T0-901317-induced ACCalpha expression by decreasing the transcriptional activity of LXR and SREBP-1 and that ERK1/2 and p38MAPK are components of the signaling pathway mediating the inhibitory effects of CDCA on ACCalpha expression and triglyceride secretion

Tailoring the defects and electronic band structure in WS2/h-BN heterostructure

The 2D semiconducting transition metal dichalcogenides (e.g., WS2) host strong coupling between various degrees of freedom leading to potential applications in next-generation device applications including optoelectronics. Such applications are strongly influenced by defects which can control both the optical and electronic properties of the material. We demonstrate the possibility to tailor the defect-related electronic states and the lattice dynamics properties of WS2 in their heterostructures with h-BN which host a strong interlayer coupling between the charge carriers in the WS2 layer and the phonons of h-BN. This coupling is observed to induce modifications to the interlayer phonons (manifested by their modified Raman-activity) and to the charge carrier mobilities in the WS2 layer (which results in creation of mid-gap energy states associated with many-body quasiparticle states). Our study also includes a detailed characterization of the defects through Raman measurements revealing an A_1g-type nature with differential resonance behavior for the modes that are related to defect scattering with respect to the other normal phonon modes of WS2.Comment: 22 pages, 5 figures, Supplemental materia

Osteopontin Is Required for the Early Onset of High Fat Diet-Induced Insulin Resistance in Mice

Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined.We initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2-4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro.The OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance

GPR105 Ablation Prevents Inflammation and Improves Insulin Sensitivity in Mice with Diet-Induced Obesity

GPR105, a G-protein coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Since inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that UDP-Glc enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma UDP-Glc levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence, GPR105 provides a novel link between innate immunity and metabolism

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation

NCoR Repression of LXRs Restricts Macrophage Biosynthesis of Insulin-Sensitizing Omega 3 Fatty Acids

SummaryMacrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies

Photoreceptor glucose metabolism determines normal retinal vascular growth

Abstract The neural cells and factors determining normal vascular growth are not well defined even though vision‐threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet‐derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon‐induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia‐associated retinal abnormalities and suppress phase I ROP in premature infants