Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: A link to obesity

Mitochondrial dysfunction is the cause of a variety of pathologies associated with high energy- requiring tissues like the brain and muscles. Here we show that aluminum ( Al) perturbs oxidative- ATP production in human hepatocytes ( HepG2 cells). This Al- induced mitochondrial dysfunction promotes enhanced lipogenesis and the accumulation of the very low density lipoprotein ( VLDL). Al- stressed HepG2 cells secreted more cholesterol, lipids and proteins than control cells. The level of apolipoprotein B- 100 ( ApoB-100) was markedly increased in the culture medium of the cells exposed to Al. C-13- NMR and HPLC studies revealed a metabolic profile favouring lipid production and lowered ATP synthesis in Al- treated cells. Electrophoretic and immunoblot analyses pointed to increased activities and expression of lipogenic enzymes such as glycerol 3- phosphate dehydrogenase ( G3PDH), acetyl CoA carboxylase ( ACC) and ATP- citrate lyase ( CL) in the hepatocytes exposed to Al, and a sharp diminution of enzymes mediating oxidative phosphorylation. D- Fructose elicited the maximal secretion of VLDL in the Al-challenged cells. These results suggest that the Al-evoked metabolic shift favours the accumulation of lipids at the expense of oxidative energy production in hepatocytes.