Decreased expression of the plasma membrane
citrate transporter INDY (acronym I'm Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing
citrate import into hepatocytes by different strategies can reduce hepatic
triglyceride accumulation and improve hepatic
insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo
fatty acid biosynthesis as a result of reduced cytoplasmic
citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular
lipid accumulation,
body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral
catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both
metabolic disease and blood pressure control.