INSIG-2 Activators

Chemicals that can activate INSIG-2 or the related pathways operate primarily by modulating lipid metabolism and cholesterol biosynthesis. Statins including atorvastatin, lovastatin, and simvastatin inhibit HMG-CoA reductase, reducing intracellular cholesterol. This reduction can stimulate SREBP pathway, triggering INSIG-2 upregulation to compensate for the reduced cholesterol levels. Similarly, mevalonate, a key intermediate in cholesterol biosynthesis and U18666A, a cholesterol transport inhibitor, can increase the demand for cholesterol synthesis or cause cholesterol accumulation in the endoplasmic reticulum, respectively. These changes can activate the SREBP pathway, leading to INSIG-2 upregulation to meet the increased demand for cholesterol.

25-Hydroxycholesterol, an oxysterol product, can activate the SREBP pathway and increase INSIG-2 activity as part of the cellular response to cholesterol overload. In contrast, geranylgeraniol and farnesol, products of the cholesterol synthesis pathway, can alter the SREBP pathway and potentially upregulate INSIG-2. AMPK activators, such as metformin and AICAR, can activate AMPK leading to SREBP inhibition. This inhibition can cause a compensatory upregulation of INSIG-2 to maintain cholesterol homeostasis. Similarly, PPAR-γ agonists like pioglitazone and rosiglitazone can alter lipid metabolism and potentially upregulate INSIG-2.