Pharmacological inhibition of mINDY for the treatment of NAFLD/NASH
PhD student: Nermeen Elagroudy
Supervisor at TUD: Tiago C. Alves, Andreas Birkenfeld
Supervisor at KCL: Geltrude Mingrone
Start date: 01.09.2017 Date of defense: 25.11.2021 Joint PhD
Non-Alcoholic Fatty Liver Disease or NAFLD is one of the leading causes of chronic liver disease worldwide without any FDA approved therapies. Non-Alcoholic SteatoHepatitis (NASH), an advanced stage of the disease, has currently reached the second most indication of liver transplantation in US and Europe. Despite the complexity of NAFLD pathophysiology, metabolic dysregulation is among the main drivers for the disease development and progression. The plasma membrane citrate transporter mammalian INDY (mINDY, acronym for I’m Not Dead Yet) is significantly increased in livers of human and mice with NAFLD, disrupting glucose and lipid metabolism and contributing to the accumulation of lipid toxic species, lipotoxicity as well as insulin resistance, the key NAFLD pathogenic hits. Therefore, mINDY was proposed as a potential drug target for NAFLD and metabolic-related disorders. The main goal of this study was to test this hypothesis and determine whether we could introduce mINDY inhibitors as a new therapeutic class, not only for non-alcoholic fatty liver (NAFL) but also for the more advanced stage of the disease, NASH and the associated fibrosis.
Accordingly, we tested a mINDY inhibitor (mINDYi) in a NASH mouse model induced by a lipid rich western diet (WD) feeding. This diet causes hyperglycemia, hyperinsulinemia, hepatic steatosis, inflammation and injury as evident by elevated plasma transaminases, together with hepatocellular ballooning and fibrosis in at least 60% of the mice after 16 weeks of feeding. Our results show that mice treated with mINDYi had reduced body weight, fat mass and increased lean mass compared to vehicle-treated mice. Moreover, our study demonstrates for the first time that mINDYi treatment attenuates WD-induced glucose intolerance, insulin resistance, hepatic lipid accumulation, inflammatory cell infiltration and liver injury, yet without apparent effect on fibrosis deposition. Interestingly, we found that modulating hepatocellular citrate uptake affects fibroblast growth factor 21 (Fgf21) transcription, a hepatokine that has been shown to have beneficial effects against NASH. Reduction in hepatic citrate uptake by mINDYi in vitro and in vivo increased plasma and hepatic expression of Fgf21. This was accompanied by increased hepatic expression of different Fgf21 transcriptional regulators including SIRT-1, as well as increased LKB1 and AMPK phosphorylation suggesting enhanced hepatic Fgf21 downstream signaling. We postulate that induction of hepatic Fgf21-AMPK signaling could be the mechanism by which mINDYi mediates NASH attenuation, at least in part. To conclude, we provide the first ‘Proof-of-Concept’ study for the therapeutic potential of mINDY inhibitors in NAFLD/NASH; paving the road for future preclinical research on this class of inhibitors. Further investigations are currently ongoing to expand our understanding of the molecular mechanisms underlying mINDY inhibition and the observed NASH attenuation.
Publications:
Are Lifestyle Therapies Effective for NAFLD Treatment? N.N. El-Agroudy*, A. Kurzbach*, R.N. Rodionov, J. O'Sullivan, M. Roden, A.L. Birkenfeld, D.H. Pesta. Trends Endocrinol Metab. 2019;30:701-709.
Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus. C. Henke, K. Tollner, R.M. van Dijk, N. Miljanovic, T. Cordes, F. Twele, S. Broer, V. Ziesak, M. Rohde, S.M. Hauck, C. Vogel, L. Welzel, T. Schumann, D.M. Willmes, A. Kurzbach, N.N. El-Agroudy, S.R. Bornstein, S.A. Schneider, J. Jordan, H. Potschka, C.M. Metallo, R. Kohling, A.L. Birkenfeld, W. Loscher. Neurobiol Dis. 2020;143:105018.
Protection from doxorubicin-induced nephrotoxicity by clindamycin: novel antioxidant, anti-inflammatory and anti-apoptotic roles. K.M. Ibrahim, E.M. Mantawy, M.M. Elanany, H.S. Abdelgawad, N.M. Khalifa, R.H. Hussien, N.N. El-Agroudy, E. El-Demerdash. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:739-748.
Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance. T. Schumann, J. König, C. von Loeffelholz, D.F. Vatner, D. Zhang, R.J. Perry, M. Bernier, J. Chami, C. Henke, A. Kurzbach, N.N. El‑Agroudy, D.M. Willmes, D. Pesta, R. de Cabo, J.F. O Sullivan, E. Simon, G.I. Shulman, B.S. Hamilton, A.L. Birkenfeld. Commun Biol. 2021;4(1):826.
The longevity gene mIndy (I'm Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms. D.M. Willmes, M. Daniels, A. Kurzbach, S. Lieske, N. Bechmann, T. Schumann, C. Henke, N.N. El-Agroudy, A.C. Da Costa Goncalves, M. Peitzsch, A. Hofmann, W. Kanczkowski, K. Kräker, D.N. Müller, H. Morawietz, A. Deussen, M. Wagner, A. El-Armouche, S.L. Helfand, S.R. Bornstein, R. de Cabo, M. Bernier, G. Eisenhofer, J. Tank, J. Jordan, A.L. Birkenfeld. JCI Insight. 2021;6(2):136083.