Team:BGU Israel/Project/Aspiration Shift

One of most serious effects of unbalanced fat metabolism is an abnormal accumulation of fatty acids in non-adipose tissues, particularly skeletal muscles and liver. This effect is strongly associated with insulin resistance and obesity. One of the key members, which can reduce abnormal fat accumulation, is peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear hormone receptor family of ligand-activated transcription factors. Activation of this receptor increases the expression of genes important to fatty acid oxidation, lipid transport and mitochondrial biogenesis processes(Aharoni-simon, Hann-obercyger, Pen, Madar, & Tirosh, 2011). In vivo induction of the PPARγ co-activator 1α (PGC-1α) showed a high level of fatty acid oxidation capacity.

However, overexpression of PGC-1α also induced insulin resistance(Benton, Holloway, Han, & Yoshida, 2010). In vivo induction of the PPARγ coactivator 1α (PGC-1α) shows increased insulin-sensitizing effects and a high level of oxidative capacity. However, overexpression of PGC-1α induced insulin resistance (Benton, Holloway, Han, & Yoshida, 2010).

In order to prevent this phenomenon, we designed a self-regulating mechanism, which leads to modest overexpression of PGC-1α, shown in figure 1. We chose sterol regulatory elements (SRE) to promote the expression of PGC-1α. When the cell is in an anabolic state, i.e. accumulating fatty acids, a transcription factor called SREBP (Sterol Regulatory Element-Binding, Proteins) is expressed (Shimomura, Bashmakov, & Horton, 1999). As its name suggests, the SREBP binds the sterol regulatory elements and induce the expression of PGC-1α. 
In order to limit the expression of PGC-1α and prevent supra-physiological overexpression, we add a PPARγ sensitive promoter which controls the expression of a repressor which binds to an operator downstream the sterol regulatory elements. This way, PGC-1α inhibits its own expression and stays in a modest physiological concentration.

Click on the picture to check out the machanism

Figure 1 – SREBP serves as a molecular indicator for fat accumulation in the cell and induces the expression of PGC1-α by binding to the sterol regulatory elements in our construct (SRE). PGC1-α then activates a negative feedback loop, inhibiting its own expression. The result is a modest expression of PGC1-α in the cell.