Volume 14, Issue 2, Pages (August 2011)

Slides:



Advertisements
Similar presentations
Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis Jussi Pihlajamäki, Carles Lerin, Paula.
Advertisements

Volume 14, Issue 6, Pages (December 2011)
Volume 9, Issue 3, Pages (March 2009)
The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1
Volume 18, Issue 3, Pages (September 2013)
Volume 24, Issue 6, Pages (December 2016)
Volume 20, Issue 5, Pages (November 2014)
FGF21 Is an Exocrine Pancreas Secretagogue
Volume 15, Issue 2, Pages (February 2012)
Volume 11, Issue 4, Pages (April 2010)
Volume 12, Issue 4, Pages (October 2010)
Volume 21, Issue 11, Pages (December 2017)
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
Volume 2, Issue 2, Pages (August 2005)
Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent Termination  Konstantina Skourti-Stathaki, Nicholas J.
Volume 7, Issue 3, Pages (March 2008)
Volume 24, Issue 4, Pages (October 2016)
Volume 15, Issue 5, Pages (May 2012)
Volume 9, Issue 6, Pages (June 2009)
Volume 13, Issue 8, Pages (November 2015)
Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo
Volume 2, Issue 5, Pages (November 2005)
Volume 16, Issue 7, Pages (August 2016)
Volume 9, Issue 6, Pages (June 2009)
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
Volume 1, Issue 2, Pages (February 2005)
Volume 16, Issue 4, Pages (October 2012)
Volume 9, Issue 5, Pages (May 2009)
Volume 14, Issue 5, Pages (November 2011)
Volume 10, Issue 1, Pages (July 2009)
Volume 6, Issue 4, Pages (October 2007)
Volume 10, Issue 5, Pages (November 2009)
Volume 8, Issue 2, Pages (August 2008)
Volume 19, Issue 2, Pages (February 2014)
Volume 8, Issue 4, Pages (October 2008)
Volume 14, Issue 1, Pages (July 2011)
Volume 16, Issue 4, Pages (October 2012)
Volume 6, Issue 3, Pages (September 2007)
Volume 9, Issue 6, Pages (December 2014)
Volume 18, Issue 1, Pages (July 2013)
Volume 6, Issue 1, Pages (July 2007)
Joseph T. Rodgers, Wilhelm Haas, Steven P. Gygi, Pere Puigserver 
Volume 14, Issue 4, Pages (October 2011)
Volume 9, Issue 3, Pages (March 2009)
Volume 16, Issue 2, Pages (August 2012)
Volume 10, Issue 6, Pages (December 2009)
Volume 21, Issue 3, Pages (March 2015)
Volume 15, Issue 6, Pages (June 2012)
Volume 9, Issue 5, Pages (May 2009)
High-Fat Diet Triggers Inflammation-Induced Cleavage of SIRT1 in Adipose Tissue To Promote Metabolic Dysfunction  Angeliki Chalkiadaki, Leonard Guarente 
Volume 8, Issue 5, Pages (November 2008)
Volume 21, Issue 2, Pages (February 2015)
Volume 14, Issue 2, Pages (August 2011)
Volume 13, Issue 4, Pages (April 2011)
Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice  Decheng Ren, Minghua Li, Chaojun Duan, Liangyou.
Volume 129, Issue 2, Pages (April 2007)
Xiaoyue Pan, Yuxia Zhang, Li Wang, M. Mahmood Hussain  Cell Metabolism 
Knockdown of MPST weakens JNK phosphorylation, ameliorates hepatic oxidative stress and suppresses the release of MCP-1. Knockdown of MPST weakens JNK.
Negative Regulation of Tumor Suppressor p53 by MicroRNA miR-504
Volume 16, Issue 4, Pages (October 2012)
Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis
Volume 49, Issue 2, Pages (January 2013)
A Long Non-coding RNA, lncLGR, Regulates Hepatic Glucokinase Expression and Glycogen Storage during Fasting  Xiangbo Ruan, Ping Li, Andrew Cangelosi,
Volume 9, Issue 4, Pages (April 2009)
Volume 11, Issue 3, Pages (March 2010)
Volume 24, Issue 6, Pages (December 2016)
A Splicing-Independent Function of SF2/ASF in MicroRNA Processing
Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice  Jun Yoshino, Kathryn F. Mills,
The GCN2 eIF2α Kinase Regulates Fatty-Acid Homeostasis in the Liver during Deprivation of an Essential Amino Acid  Feifan Guo, Douglas R. Cavener  Cell.
Volume 1, Issue 5, Pages (May 2005)
Presentation transcript:

Volume 14, Issue 2, Pages 208-218 (August 2011) Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis  Jussi Pihlajamäki, Carles Lerin, Paula Itkonen, Tanner Boes, Thomas Floss, Joshua Schroeder, Farrell Dearie, Sarah Crunkhorn, Furkan Burak, Josep C. Jimenez-Chillaron, Tiina Kuulasmaa, Pekka Miettinen, Peter J. Park, Imad Nasser, Zhenwen Zhao, Zhaiyi Zhang, Yan Xu, Wolfgang Wurst, Hongmei Ren, Andrew J. Morris, Stefan Stamm, Allison B. Goldfine, Markku Laakso, Mary Elizabeth Patti  Cell Metabolism  Volume 14, Issue 2, Pages 208-218 (August 2011) DOI: 10.1016/j.cmet.2011.06.007 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 RNA-Processing Gene Expression Is Downregulated in Obesity (A) Top-ranking downregulated pathways in obese humans are identified through GO-based pathway analysis (MAPPFinder) of microarray data from liver and muscle. (B) Heatmap of 13 RNA-processing genes with decreased gene expression in both tissues. Blue indicates lower and red higher gene expression. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; T2D, type 2 diabetes. (C) Expression of RNA-processing genes was determined by real-time PCR from mouse liver and muscle after 4 months of HFD (black bars) compared to chow diet (white bars). Data are mean ± SEM. ∗, p < 0.05 versus chow (n = 6). (D) Protein levels of SFRS10, SFPQ, and HNRPK were measured by western blot from liver nuclear extracts. See Figure S1. Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 2 SFRS10 Knockdown Increases Expression of Lipogenic Genes and Leads to TAG Accumulation in Hepatic Cells (A) (All panels) HepG2 cells were transfected with scramble (SCR) or SFRS10 siRNA and analyzed 4 days later. SFRS10 mRNA and protein levels were analyzed by real-time PCR and Western blot (A). (B) mRNA levels were determined by real-time PCR. (C–F) Lipogenesis (from 14C-acetate) (C), TAG levels (D), TAG synthesis (E), and fatty acid oxidation (F) were measured as described in Experimental Procedures. Data are mean ± SEM of triplicates, representative of three independent experiments. ∗, p < 0.05 versus SCR siRNA. See Figure S2. Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 3 Sfrs10 Heterozygous Mice Show Increased Lipogenic Gene Expression and Hypertriglyceridemia (A) (All panels) Wild-type (WT) and Sfrs10 heterozygous (Het) mice were fasted for 16 hr and then refed for 10 hr before sacrifice. Liver Sfrs10 mRNA and protein levels were determined by real-time PCR and western blot (A). (B) Liver mRNA was quantified by real-time PCR. (C and D) Liver TAG (C) and plasma TAG (D) were measured as in Experimental Procedures. (E) Plasma lipoprotein profile was determined by FPLC. (F) VLDL secretion was calculated by quantifying plasma TAG after Tyloxapol administration. Data are mean ± SEM of at least five mice/group and are representative of two independent cohorts. ∗, p < 0.05 versus WT. See Figure S4. Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 4 SFRS10 Regulates LPIN1 Splicing (A) The putative binding site of SFRS10, GGAA, is highlighted in gray within alternatively spliced exon 6 sequence (Ensembl release 61) of human and mouse LPIN1. The U1 snRNA binding site at the 5′ splice site is underlined. (B) SFRS10 cotransfection increases exclusion of LPIN1 exon 6 in a minigene system (left), while SFRS10 siRNA increases inclusion (right). PCR primers are shown as arrows. (C and D) Expression of total LPIN1, LPIN1β, and LPIN1α isoforms was determined (real-time PCR) in: HepG2 cells after SCR (white bars) or SFRS10 siRNA (black bars) (C), and liver samples from WT (white, n = 7) and Sfrs10 heterozygous (black, n = 5) mice (D). (E–G) Expression of Lpin1β relative to Lpin1α was measured by real-time PCR in liver from: HFD (black, n = 6) and chow (white, n = 6) mice (E), lean (white, n = 6) or obese (black, n = 14) humans (F), and Hepa1c cells after GFP (white, n = 5) or SFRS10 (black, n = 5) overexpression (G). Data are mean ± SEM. ∗, p < 0.05 versus control. See Figure S2. Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 5 Increased Expression of Lipogenic Genes and Lipogenesis in Response to SFRS10 siRNA Is Reversed with LPIN1β Knockdown (A–D) HepG2 cells were transfected with the indicated siRNA and analyzed 4 days later. mRNA levels were determined by real-time PCR (A). Lipogenesis (B), TAG accumulation (C), and lysophosphatidic acid levels (D) were measured as in Experimental Procedures. Data are mean ± SEM of triplicates, representative of three independent experiments. ∗, p < 0.05 versus SCR siRNA. #, p < 0.05 versus SFRS10 siRNA. See Figure S5. Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 6 Human Obesity Is Associated with Decreased Expression of RNA-Processing Genes and Can Influence Metabolic Phenotypes Reduced expression of the splicing factor SFRS10 alters splicing of LPIN1, leading to dysregulation of lipogenic pathways and contributing to hypertriglyceridemia. Other alterations in RNA processing in human obesity should be identified (dashed arrows). Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell Metabolism 2011 14, 208-218DOI: (10.1016/j.cmet.2011.06.007) Copyright © 2011 Elsevier Inc. Terms and Conditions