B10 - Lipid accumulation mechanisms and their modulation

We will use lipoma to model aberrant lipid accumulation and inhibit target molecules identified in the previous funding period (PIK3CA, PDE3/4/8, MAOA). Further, we will inquire about sequencing data from human lipomas and human obesity databases to identify novel genes involved in adipocyte development and lipid accumulation. We will assess whole-body energy metabolism and characterize differences in adipose tissue between lipoma-bearing and control mice to identify factors involved in adipose tissue remodeling.

Figure: 1A: Schematic overview of the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway which is constitutively active under conditions of phosphatase and tensin homolog (PTEN) haploinsufficiency caused by PTEN germline mutations. 1B: Adipose tissue sections from a lipoma of a patient with PTEN mutation (left) and age-matched control (right). Scale bar = 100 µm 1C: Quantification of adipocyte size in adipose tissue sections of patients with PTEN or PI3K mutations and age-matched controls.

Kässner F, Kirstein A, Händel N, Schmid GL, Landgraf K, Berthold A, Tannert A, Schaefer M, Wabitsch M, Kiess W, Körner A, Garten A. A New Human Adipocyte Model With PTEN Haploinsufficiency. Adipocyte. 2020 Dec;9(1):290-301.


Le Duc D, Lin CC, Popkova Y, Yang Z, Akhil V, Çakir MV, Grunewald S, Simon JC, Dietz A, Dannenberger D, Garten A, Lemke JR, Schiller J, Blüher M, Nono Nankam PA, Rolle-Kampczyk U, von Bergen M, Kelso J, Schöneberg T. Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity. Int J Obes (Lond). 2020 Nov 24.


Kirstein A, Augustin A, Penke M, Cea M, Körner A, Kies W, Garten A.The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells. Cancers (Basel). 2019 Oct 17;11(10)


Buhl JP, Garten A, Kratzsch J, Kiess W, Penke M. How Reliable are Commercially Available Glypican4 ELISA Kits? Exp Clin Endocrinol Diabetes. 2020 Oct 16.  


Bohn C, Vogel M, Spielau U, Hilbert C, Kiess W, Körner A. Birth weight increases with birth order despite decreasing maternal pregnancy weight gain. Acta Paediatrica 2020 Sept.


Garten A, Grohmann T, Kluckova K, Lavery GG, Kiess W, Penke M. Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1. Int J Mol Sci. 2019 Aug 19;20(16). pii: E4048.


Sociali G, Grozio A, Caffa I, Schuster S, Becherini P, Damonte P, Sturla L, Fresia C, Passalacqua M, Mazzola F, Raffaelli N, Garten A, Kiess W, Cea M, Nencioni A, Bruzzone S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 2018 Dec 4:fj201800321R.


Grohmann T, Penke M, Petzold-Quinque S, Schuster S, Richter S, Kiess WGarten A. Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway. Leukemia Res. 2018 Jun,69, 39–46.


Kässner F, Sauer T, Penke M, Richter S, Landgraf K, Körner A, Kiess W, Händel N, Garten A.Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells. Int J Mol Med. 2018 Mar 14.


Penke M, Schuster S, Gorski T, Gebhardt R, Kiess WGarten A. Oleate ameliorates palmite-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells. Lipids Health Dis. 2017;16:191.


Leipert J, Kässner F, Schuster S, Händel N, Körner A, Kiess W, Garten A. Resveratrol potentiates growth inhibitory effects of rapamycin in PTEN-deficient lipoma cells by suppressing p70S6 kinase activity. Nutr Cancer. 2016;68:342-9.


Wilhelm F, Kässner F, Schmid G, Kratzsch J, Laner A, Wabitsch M, Körner A, Kiess W, Garten A. Phosphatidylinositol 3-kinase (PI3K) signalling regulates insulin-like-growth factor binding protein-2 (IGFBP-2) production in human adipocytes. Growth Horm IGF Res. 2015;25:115-20.


Schmid GL, Kässner F, Uhlig HH, Körner A, Kratzsch J, Händel N, Zepp FP, Kowalzik F, Laner A, Starke S, Wilhelm FK, Schuster S, Viehweger A, Hirsch W, Kiess W, Garten A. Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies. Pediatr Res. 2014;75:527-34.

 

PROJECT LEADERS

Doctoral Researcher

Anna Kirstein

Office address:
Room No. 3012,  Liebigstr.12, 04103 Leipzig
Phone (lab or office):
E-mail
+49 341 9726504
 
PhD project description:
Lipomas in children with PTEN germline mutations (PHTS patients) can lead to life threatening complications. We investige mechanisms leading to this aberrant adipose tissue growth and test new treatment options for patients with PHTS in lipoma cell models. The research includes work with human and mouse adipose tissue, primary cell culture work and CRISPR/Cas gene editing.