Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE14921 | GEO | 2009/04/07
SECONDARY ACCESSION(S): PRJNA111907
REPOSITORIES: GEO
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Project description:Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator activated receptor (PPAR ) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism. SIRT4 knockout (KO) and wild-type (WT) littermates (male; n 6 per genotype; 7- to 8-month-old littermates) were sacrificed after a 16-h overnight fast. Samples were individually hybridized on Affymetrix Mouse Genome 430 2.0 GeneChips by the Biopolymers Facility (Harvard Medical School).
2014-03-28 | E-GEOD-56321 | biostudies-arrayexpress
Project description:Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator activated receptor (PPAR ) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.
2014-03-28 | GSE56321 | GEO
Project description:HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3; trade name “GenX”) is an alternative to environmentally persistent per- and poly-fluorinated alkyl substances (PFAS). The liver is the primary target of toxicity for HFPO-DA in rodents and previous examination of hepatic transcriptomic responses in mice following oral exposure to HFPO-DA for 90 days showed induction of peroxisome proliferator-activated receptor (PPAR) signaling pathways, predominantly by PPAR alpha, as well as increased gene expression of both peroxisomal and mitochondrial fatty acid metabolism. To further investigate the mechanism of liver toxicity, transcriptomic analysis was conducted on liver tissue from mice orally exposed to 0, 0.1, 0.5 or 5 mg/kg-bw/day HFPO-DA in a reproduction/developmental toxicity study. Hepatic gene expression changes were consistent with the previous 90-day mouse study, demonstrating activation of the PPAR alpha signaling pathway. Peroxisomal and mitochondrial fatty acid beta-oxidation gene sets were enriched at lower HFPO-DA concentrations, and complement cascade, cell cycle and apoptosis related gene sets were enriched at higher HFPO-DA concentrations. These results support the reported histopathological findings in livers of mice from this study and indicate that these effects are mediated through rodent-specific PPAR alpha signaling mechanisms.
2022-06-08 | GSE202302 | GEO
Project description:To test whether NDGA attenuate dyslipidemia and hepatic steatosis by enhancing fatty acid oxidation through activation of PPAR-α. Using wild type (WT, C57BL/6) fed with chow diet as control, WT mice were either fed with high-fat diet or high-fat diet with NDGA (2.5g/kg food); ob/ob mice were fed with either chow or chow with NDGA (2.5 g/kg food), and maintained on the respective diets for 16 weeks. The expression of lipid metabolism related genes in the liver of these mice were analyzed using Phalanx GPL6845 platform (Mouse OneArray V1). Together with other biochemical/physiological data, our results suggest that the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation and energy utilization via the activation of PPAR- α receptor activity. To examine the changes in gene expression in liver of WT and ob/ob mice with different NDGA diet treatment, RNA isolated from 3 animals of each group were used for studies of gene expression profiles. Phalanx GPL6845 platform (Mouse OneArray V1) was used for the microarrays analysis.
2012-03-29 | E-GEOD-35075 | biostudies-arrayexpress
Project description:The goal of this project is to understand how the phosphorylation status of T522 at SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, regulates its activity and function in vivo. We have previously reported that SIRT1 can be phosphorylated and activated by two anti-apoptotic members of the dual specificity tyrosine phosphorylation-regulated kinase (DYRK), DYRK1A and DYRK3, in response to acute environmental stresses. However, whether this modification is involved in regulation of SIRT1 activity remains elusive. To assess the physiological impacts of the phosphorylation of T522 on SIRT1, we generated SIRT1 T522 phosphorylation mimic (T522E mutation, or TEKI) and dephosphorylation mimic (T522A mutation, or TAKI) knock-in mouse models. Our current findings indicated that TAKI mice but not TEKI mice displayed impaired hepatic fatty acid oxidation and developed hepatic steatosis after high-fat diet feeding. To understand the molecular mechanisms underlying this phenotype, we examined the hepatic transcriptomes of SIRT1 WT, TAKI and TEKI mice after 5-month high-fat diet feeding by microarray analysis.
2017-02-22 | GSE94904 | GEO
Project description:To test whether NDGA attenuate dyslipidemia and hepatic steatosis by enhancing fatty acid oxidation through activation of PPAR-α. Using wild type (WT, C57BL/6) fed with chow diet as control, WT mice were either fed with high-fat diet or high-fat diet with NDGA (2.5g/kg food); ob/ob mice were fed with either chow or chow with NDGA (2.5 g/kg food), and maintained on the respective diets for 16 weeks. The expression of lipid metabolism related genes in the liver of these mice were analyzed using Phalanx GPL6845 platform (Mouse OneArray V1). Together with other biochemical/physiological data, our results suggest that the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation and energy utilization via the activation of PPAR- α receptor activity.
2012-03-30 | GSE35075 | GEO
Project description:*Objectives:* In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Genome wide association studies identified SNPs near the cell cycle regulator CDKN2A/p16INK4a (p16) as strongly associated with risk of developing type 2 diabetes (T2D). T2D is associated with numerous perturbations of hepatic lipid and glucose metabolism. We have recently shown that p16 controls fasting-induced hepatic gluconeogenesis in mice. However, whether p16 may also affect hepatic lipid homeostasis is unknown. *Results:* In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism and enhanced activation of PPAR. This led to increased mitochondrial fatty acid oxidation (FAO) through a mechanism requiring the catalytic AMPK 2 subunit and SIRT1. By contrast, *p16* overexpression was associated with triglyceride accumulation and increased lipid droplet numbers *in vitro*, and decreased ketogenesis and hepatic mitochondrial activity *in vivo*. Gene expression analysis of human liver samples revealed a negative correlation between *CDKN2A* expression and *PPARA* and its target genes, suggesting a potential association between hepatic p16 expression and FAO in obese humans. *Conclusions:* Our findings demonstrate that p16 plays a key role in hepatic lipid metabolism and may thus contribute to the development of metabolic diseases.
2020-10-09 | GSE134625 | GEO
Project description:Exposure to PFOA during gestation altered the expression of genes related to fatty acid catabolism in both the fetal liver and lung. In the fetal liver, the effects of PFOA were robust and also included genes associated with lipid transport, ketogenesis, glucose metabolism, lipoprotein metabolism, cholesterol biosynthesis, steroid metabolism, bile acid biosynthesis, phospholipid metabolism, retinol metabolism, proteosome activation, and inflammation. These changes are consistent with activation of PPAR alpha. Non-PPAR alpha related changes were suggested as well. Keywords: gene expression, microarray,PFOA, mouse, fetus, liver
2008-10-07 | GSE13044 | GEO
Project description:In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+ a co-substrate of the class III histone deacetylase SIRT1 that associates with clock transcription factors. While NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during nighttime display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by BMAL1 and PPARa and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.
2021-10-08 | GSE151281 | GEO
Project description:Our project focuses on retinoic acid (RA) effect on hepatic lipid homeostasis. Even though RA has more than one receptor including retinoids x receptor (RXR) and retinoic acid receptor (RAR), most probably, RA effect on lipid homeostasis is mediated by RXR and its partners such as PXR, FXR, and PPAR. So we treated the wild type and RXRα-knockout mice by retinoic acid to check the global gene expression especially for lipid homeostasis genes. We used microarrays to observe the global gene expression underlying hepatic lipid homeostasis. We treated both the wild type and RXRα-KO mice with normal diet and RA-containing diet for 7 days. For each group, three replicates were done. Liver total RNA were used to test global gene expression by microarray.
2013-08-21 | E-GEOD-50028 | biostudies-arrayexpress