Mitochondrial VDAC: A New Strategy for Fighting Steatosis and NASH
Introduction
The mitochondrial channel VDAC1 is a multi-functional protein that mediates the flux of nucleotides, metabolites, hemes, fatty acids, cholesterol, ROS and ions, including Ca2+, across the outer mitochondrial membrane (OMM). VDAC1 also serves as a convergence point for a variety of cell survival and cell death signals and which plays a pivotal role in cellular energetic pathways. Considered a hub protein, VDAC1 interacts with >150 proteins that regulate the integration of mitochondrial functions with other cellular activities. Thus, VDAC1 serves as a mitochondrial gatekeeper, controlling metabolic and energetic cross-talk between mitochondria and the rest of the cell and a key player in mitochondria-mediated apoptosis. VDAC1, also shown to activate fatty acid oxidation, with mitochondria lacking VDAC1 are no longer able to oxidize substrates. Finally, inhibiting VDAC1 activity also inhibited palmitate oxidation.
The Technology
We selected a cell-penetrating peptide comprising a VDAC1-derived sequence containing residues in the D-configuration fused with a cell-penetrating sequence (“the Compound”).
In a STAM mouse model in which NASH was induced by a single sub-cutaneous injection of a low dose of streptazotocin followed by a high-fat diet, intravenous or intramuscular delivery of the compound inhibited steatosis and NASH development. Inflammation and fibrosis of liver tissue were also largely eliminated by the treatment. The fat that accumulates in the liver in steatosis and NASH was not seen in the compound-treated mice, as revealed by oil red staining. In addition, the compound increased the number of Langerhans islets, as visualized using anti-insulin antibodies.
Suggested mode of action: The compound increase fatty acid oxidation, revealed both in-vitro in cultured cells and in-vivo. At the outer mitochondrial membrane, VDAC1 interacts with CPT1 (carnitine palmitoyltransferase 1a) and ACSL (long-chain acyl-CoA synthetase). By modulating these interactions, the compound stimulates fatty acids translocation to the mitochondria and their oxidation.
Advantages
- Compound has been optimized for activity at low concentrations and high stability.
- The mode of activity and POC efficacy has been established and validated in-vitro and invivo.
- The compound has a safe profile with no effect on WT mice.
- The compound can be administrated intravenous and also intramuscular.
Patent Status
PCT patent No. IL2016/050958 filed September 2015.
Principal Investigator
Prof. Varda Shoshan-Barmatz, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel.