Yang, N. V.; Chao, J. Y.; Garton, K. A.; Tran, T.; King, S.; Orr, J.; Oei, J. H.; Kang, M.; Zalpuri, R.; Jorgens, D. M.; Konchadi, P.; Chorba, J. S.; Theusch, E.; Krauss, R. M.

The gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. Human genetic variants near APOE and TOMM40 are strongly associated with plasma lipid levels, but a specific role for TOMM40 in lipid metabolism has not been established. Investigating this, we show that suppression of TOMM40 in human hepatoma cells upregulates expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content are increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining is significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content is reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice results in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis. These findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.