Team:BGU Israel/Project/Aspiration Shift

One of the 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 order to prevent the state of insulin resistance, we designed a self-regulating mechanism, to limit overexpression of PGC-1α, as shown in figure 1. The mechanism is based on the sterol regulatory elements (SRE) to control PGC-1α expression. When cell is found 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). The SREBP binds the sterol regulatory elements and induces the expression of PGC-1α. Thus, to control PGC-1α overexpression, a PPARγ sensitive promoter controlling the expression of a repressor, which binds to an operator downstream the sterol regulatory elements, was added to the system. This way, PGC-1α inhibits its own overexpression and remains in a modest physiological level; a level which does not lead to insulin resistance.

Click on the picture to check out the machanism