INDY-A New Link to Metabolic Regulation in Animals and Humans

Abstract

The Indy (I'm Not Dead Yet) gene encodes the fly homolog of the mammalian SLC13A5 citrate transporter. Reduced expression of the Indy gene in flies and worms extends their longevity. INDY is expressed in the plasma membrane of metabolically active tissues. Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction. Reducing INDY activity prevents weight gain in flies, worms, and mice, and counteracts the negative effects of age or a high fat diet on metabolism and insulin sensitivity. The metabolic effects of reducing INDY activity are the result of reduced cytoplasmic citrate. Citrate is a key metabolite and has a central role in energy status of the cell by effecting lipid and carbohydrate metabolism and energy production. Thereby newly described drugs that reduce INDY transporting activity increase insulin sensitivity and reduce hepatic lipid levels via its effect on hepatic citrate uptake. A recent report presented the first direct link between increased hepatic levels of human INDY, insulin resistance, and non-alcoholic fatty liver disease in obese humans. Similarly increased hepatic mIndy levels were observed in non-human primates fed on a high fat diet for 2 years. This effect is mediated via the stimulatory effect of the interleukin-6/Stat3 pathway on mINDY hepatic expression. These findings make INDY a potential and very promising target for the treatment of metabolic disorders in humans.

Keywords: SLC13A5; aging; calorie restriction; longevity gene; mIndy; metabolism; non-alcoholic fatty liver disease.

FIGURE 1

Genetics and pharmacological manipulations that result in hepatic Indy reduction prevent negative effects of a high fat diet and promote health and longevity. INDY reduction increases mitochondrial biogenesis, insulin sensitivity, β-oxidation, and preserves intestinal stem cell homeostasis. Reduced INDY decreases de novo lipogenesis and hepatic lipid accumulation. Decrease in INDY transporting activity prevents fatty liver disease, insulin resistance, and weight gain.

FIGURE 2

Transcriptional regulation of hepatic mIndy mRNA levels in model organisms and humans. Hepatic mIndy expression levels are upregulated by glucagon released during early starvation via a cAMP and cAMP-responsive-element binding-protein (CREB)-dependent mechanism. A CREB binding site (C-BS) was identified in the promoter region of mINDY. Increased levels of interleukin-6 (IL-6) associated with inflammation and metabolic disease, activate transcription of hepatic mIndy via the signal transducer and activator of transcription 3 (STAT-3) signaling pathway. Diet and benzo[a]pyrene activate aryl hydrocarbon receptor (AhR) and its heterodimerization to AhR nuclear translocator (ARNT). In nucleus AhR activates transcription of mIndy via binding to potential binding site (BS) in the mIndy promoter (Neuschafer-Rube et al., 2015). Rifampicin activates the pregnane X receptor (PXR), which increases mIndy transcription by activation of two enhancer modules located upstream of the mIndy (SLC13A5) transcriptional start site (Li et al., 2015). Increased INDY levels result in higher citrate uptake and its incorporation in lipids, leading to non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2-diabetes (T2D).