Reduced expression of the Indy (‘I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. The mammalian homolog of Indy (mIndy, Slc13a5) affects hepatic lipid metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis.
Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription. Activation of the IL-6-Stat3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx and augmented hepatic lipogenesis in vivo. These data show that mIndy is increased in liver of obese humans and non-human primates with NALFD. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.
von Loeffelholz et al., The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism, Hepatology 2017 http://dx.doi.org/10.1002/hep.29089