B6 - The role of anti-inflammatory bile acids for the development and progression of non-alcoholic steatohepatitis (NASH)

B06_Heeren_FP3

Principal Investigator:
Prof. Dr. rer. nat. Joerg Heeren
Institute for Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Germany
Phone: +49-40-7410-54745
Fax: +49-40-7410-54592
E-Mail: heeren@uke.uni-hamburg.de

Participating staff:

Dr. rer. nat. Ludger Scheja – PostDoc
Dr. rer. nat. Klaus Tödter – PostDoc
Sandra Ehret – TA

Project description

Obesity-associated insulin resistance and hepatic lipid accumulation as a result of inactivity and high caloric intake are associated with the development of NASH. By exploring the therapeutic potential of increased energy expenditure using activation of thermogenic brown adipose tissue (BAT), we observed a profound up-regulation of cholesterol processing and conversion to bile acids via the alternative bile acid synthesis pathway. These processes were accompanied by reduced steatosis and hepatic inflammation. In the next funding period, we want to investigate whether increased energy expenditure inhibits the progression of NASH through anti-inflammatory properties of bile acids generated via the alternative synthesis pathway. We want to study whether these effects depend either directly on anti-inflammatory signaling through the receptor TGR5 that is expressed on Kupffer cells, and/or indirectly on bioactive metabolites released by an altered gut microbiome.

B6 in 60 SecondsVideoarchiv

online seit 01.12.2012
B6_Lipidspeicherung in Zellen
Figure 1: Excessive lipid accumulation in liver cells (yellow dots) can induce inflammatory pathways.

In the first funding period, we showed the central role of specific lipid species as metabolic predictors for the development of NASH in murine models and obese humans. In addition, we identified TREM-2 – a modulator of toll-like receptor signalling pathways – as a good candidate that might influence the regulation of acute and chronic inflammation in the liver. The functional importance of these lipid signatures and the role of TREM-2 as modulator of toll-like receptor signaling for the development and progression of NASH as well as viral- and autoimmune hepatitis will be investigated in the next funding period.

Related news:

Worthmann A, John C, Rühlemann MC, Baguhl M, Heinsen FA, Schaltenberg N, Heine M, Schlein C, Evangelakos I, Mineo C, Fischer M, Dandri M, Kremoser C, Scheja L,Franke A, Shaul PW, Heeren J.

Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis.
Nat Med. 2017 Jun 12. doi: 10.1038/nm.4357. [Epub ahead of print] PubMed PMID: 28604703.

Bartelt A, John C, Schaltenberg N, Berbée JFP, Worthmann A, Cherradi ML, Schlein C, Piepenburg J, Boon MR, Rinninger F, Heine M, Toedter K, Niemeier A, Nilsson SK, Fischer M, Wijers SL, van Marken Lichtenbelt W, Scheja L, Rensen PCN, Heeren J

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport
Nat Commun. 2017 Apr 19;8:15010. doi: 10.1038/ncomms15010.

Jung CS, Heine M, Freund B, Reimer R, Koziolek EJ, Kaul MG, Kording F, Schumacher U, Weller H, Nielsen P, Adam G, Heeren J, Ittrich H

Quantitative Activity Measurements of Brown Adipose Tissue at 7 T Magnetic Resonance Imaging After Application of Triglyceride-Rich Lipoprotein 59Fe-Superparamagnetic Iron Oxide Nanoparticle: Intravenous Versus Intraperitoneal Approach
Invest Radiol. 2016 Mar;51(3):194-202. doi: 10.1097/RLI.0000000000000235.

Scheja L, Heeren J

Metabolic interplay between white, beige, brown adipocytes and the liver
J Hepatol. 2016 Jan 30. pii: S0168-8278(16)00061-1. doi:10.1016/j.jhep.2016.01.025. [Epub ahead of print] Review.

Scherer T, Lindtner C, O’Hare J, Hackl M, Zielinski E, Freudenthaler A, Baumgartner-Parzer S, Tödter K, Heeren J, Krššák M, Scheja L, Fürnsinn C, Buettner C

Insulin regulates hepatic triglyceride secretion and lipid content via signaling in the brain
Diabetes. 2016 Feb 9. pii: db151552. [Epub ahead of print]

The authors Anna Worthmann and Jörg Heeren explain their publication in Nature Medicine:

Freezing helps against excess CholesterolVideoarchiv

online seit 12.06.2017