Figure 2.

Main pathways and molecules used for liver defatting. Forskolin increases the phosphorylation of perilipin 5, a cell surface component of lipid droplets, and it activates the lipolysis of triglycerides (TG), leading to the generation of diacylglycerol (DAG), monoacylglycerol (MAG), glycerol and free fatty acids (FFAs). FFAs serve as substrates for both β-oxidation in mitochondria, and TG synthesis targeted to very low-density lipoprotein (VLDL) production in the endoplasmic reticulum. The activation of β-oxidation is triggered by supplementation with L-carnitine, a substrate of carnitine palmitoyltransferase 1 (CPT1) for the entry of FFAs into mitochondria. The addition of amino acids (AAs) and choline is aimed to foster VLDL synthesis. PPARα (peroxisome proliferator-activated receptor α) agonists induce the expression of PPARα-target genes including CPT1, microsomal triglyceride transfer protein (MTTP) and apolipoprotein A1 (APOA1), which contribute to FFA β-oxidation, VLDL production and cholesterol (C) export via high-density lipoprotein (HDL) formation, respectively. MTTP, a key enzyme in VLDL production, catalyzes the transfer of triglycerides to apolipoprotein B (ApoB) in the endoplasmic reticulum. Rapamycin has a number of effects that concur to decrease steatosis including the inhibition of mTOR, which promotes lipogenesis, the induction of triglyceride secretion and of macro-autophagy, a process in which cells engulf and degrade intracellular components including lipid droplets. This process maintains organelle quality control, acts as a survival mechanism and contributes to lipid droplet removal.