Free fatty acids (FFAs) and their molecular targets. FFA toxicity occurs at multiple molecular levels. Palmitic acid and stearic acid induce Bim expression, under transcriptional control of FoxO3a. Free fatty acids can activate c-jun N-terminal kinase (JNK), and the magnitude of induction correlates with their toxicity. JNK activation leads to Bax-induced mitochondrial permeabilization. Bax can also lead to lysosomal permeabilization and apoptosis. Increased oxidation of fatty acids promotes the formation of reactive oxygen species, resulting in antioxidant depletion and oxidative stress. Toll-like receptor 4 is activated by palmitic acid and oleic acid, thus regulating inflammatory gene expression. Endoplasmic reticulum stress is also a feature of human nonalcoholic fatty liver disease and can be induced by saturated fatty acids, palmitic acid and stearic acid; however, the mechanisms are unclear.

Free fatty acids (FFAs) induce hepatocyte apoptosis. FFAs can modulate both the extrinsic and the intrinsic pathways of hepatocyte apoptosis. The saturated fatty acids, palmitic acid and stearic acid, lead to c-jun N-terminal kinase (JNK) dependent activation of the proapoptotic protein Bax, which then leads to mitochondrial permeabilization with release of cytochrome c, activation of effector caspases, and apoptosis. Palmitic acid can also activate the lysosomal pathway of apoptosis, via Bax activation and Bax-dependent lysosomal permeabilization. Furthermore, palmitic acid and stearic acid activate protein phosphatase 2A (PP2A) leading to activation of FoxO3a, and transcriptional activation of the proapoptotic protein Bim. The monounsaturated fatty acid, oleic acid, which is minimally toxic per se, imparts sensitivity to the death receptor mediated extrinsic pathway of apoptosis. Fas and TRAIL-R2 expression is induced by oleic acid treatment. TRAIL-R2 expression is under the transcriptional control of JNK in oleic acid treated cells. This sensitizes fatty hepatocytes to circulating Fas or TRAIL.