The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism

Hepatology. 2017 Aug;66(2):616-630. doi: 10.1002/hep.29089. Epub 2017 Jun 26.

Abstract

Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. 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 through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY.

Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy, Needle
  • Cells, Cultured
  • Deubiquitinating Enzymes / genetics*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Gene Expression Regulation*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Immunohistochemistry
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Lipid Metabolism / genetics*
  • Longevity / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mutation
  • RNA, Messenger / genetics
  • Sampling Studies

Substances

  • Interleukin-6
  • RNA, Messenger
  • Deubiquitinating Enzymes
  • MINDY-1 protein, human