Taking these studies together, and remembering that cholesterol gene suppression occurs in inducible PiZ mouse liver [59], zebrafish hepatocytes and HepG2 cells (reported here) it might be suggested that early in liver disease progression, before inclusion bodies form, perturbation of the E3 ligases favours partial Insig1 stabilization, SREBP2 suppression and lowered cholesterol synthesis. The gene discussed is INSIG1; the disease is liver disorder.