Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)

Pesta, Dominik; Perry, Rachel J.; Guebre-Egziabher, Fitsum; Zhang, Dongyan; Jurczak, Michael J.; Fischer-Rosinský, Antje; Daniels, Martin A.; Willmes, Diana M.; Bhanot, Sanjay; Bornstein, Stefan R.; Knauf, Felix; Samuel, Varman T.; Shulman, Gerald I.; Birkenfeld, Andreas L.

doi:10.18632/aging.100854

Cited by 39 publications

(60 citation statements)

References 39 publications

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“…Thus, a liver-specific phenotype does not require changes of whole-body fat or body weight. Recent data from another study using RNAi in rats to inhibit mINDY showed similar results [39]. However, that study did not demonstrate specificity or liver-selectivity of the investigated siRNA.…”

Section: Discussionmentioning

confidence: 62%

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

Brachs

Winkel

Tang

et al. 2016

Molecular Metabolism

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ObjectiveNon-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance.MethodsAdult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry.ResultsWithin the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight.ConclusionsWe show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition.

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Section: Discussionmentioning

confidence: 62%

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

Brachs

Winkel

Tang

et al. 2016

Molecular Metabolism

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“…mINDY‐KO mice gain less weight on a high‐fat diet (HFD) and during the aging process together with lower liver fat content and reduced insulin resistance . Furthermore, we showed that liver‐specific mIndy knockdown using antisense oligonucleotides in adult rats reduced hepatic lipid storage and enhanced hepatic insulin sensitivity upon feeding an HFD . Finally, a competitive, stereosensitive small molecule inhibitor of the mINDY transporter offered complete protection from diet‐induced glucose intolerance in mice and ameliorated diet‐induced fatty liver disease as shown by an independent research group …”

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confidence: 73%

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

et al. 2017

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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 and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non-human primates, a two 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 via the IL-6-receptor (IL-6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-Stat3 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 non-human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.

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“…In the liver, the level of cytosolic citrate is well-maintained through CIC-mediated export from the TCA cycle in mitochondria and SLC13A5-mediated uptake from the circulation (24,31). Recent studies reveal that reduced expression of SLC13A5 in mice and rats or its analogues in D. melanogaster and C. elegans resulted in a number of metabolic benefits that either protect mice from HFD-induced obesity and insulin resistance or promote longevity in fruit flies and worms (22)(23)(24)(25)32). Given the emerging significance of SLC13A5 in hepatic energy homeostasis, we sought to determine whether SLC13A5 plays a role in the growth of human hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…The biological importance of SLC13A5 was initially observed in Drosophila melanogaster and Caenorhabditis elegans, in which reduced expression of the SLC13A5 homologues (also named Indy (I'm Not Dead Yet)) extends the life span of both organisms, mimicking caloric restriction (22,23). Reduced expression of SLC13A5 protects mice and rats from high-fat diet (HFD)-induced adiposity and insulin resistance (24,25). On the other hand, up-regulation of SLC13A5 expression was observed in obese, non-alcoholic fatty liver disease patients, HFDtreated rhesus monkeys, and xenobiotic-treated human and rat hepatocytes (26 -28).…”

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confidence: 99%

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

Choi

et al. 2017

Journal of Biological Chemistry

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The solute carrier family 13 member 5 (SLC13A5), a sodiumcoupled citrate transporter, plays a key role in importing citrate from the circulation into liver cells. Recent evidence has revealed that SLC13A5 deletion protects mice from high-fat diet-induced hepatic steatosis and that mutation of the SLC13A5 orthologues in Drosophila melanogaster and Caenorhabditis elegans promotes longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, whether perturbation of SLC13A5 affects the metabolism and malignancy of hepatocellular carcinoma is unknown. Here, we sought to determine whether SLC13A5 regulates hepatic energy homeostasis and proliferation of hepatoma cells. RNAi-mediated silencing of SLC13A5 expression in two human hepatoma cell lines, HepG2 and Huh7, profoundly suppressed cell proliferation and colony formation, and induced cell cycle arrest accompanied by increased expression of cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin B1. Furthermore, such suppressive effects were also observed on the growth of HepG2 cell-derived xenografts expressing SLC13A5-shRNA in nude mice. Metabolically, knockdown of SLC13A5 in HepG2 and Huh7 cells was associated with a decrease in intracellular levels of citrate, the ratio of ATP/ADP, phospholipid content, and ATP citrate lyase expression. Moreover, both in vitro and in vivo assays demonstrated that SLC13A5 depletion promotes activation of the AMP-activated protein kinase, which was accompanied by deactivation of oncogenic mechanistic target of rapamycin signaling. Together, our findings expand the role of SLC13A5 from facilitating hepatic energy homeostasis to influencing hepatoma cell proliferation and suggest a potential role of SLC13A5 in the progression of human hepatocellular carcinoma.Metabolic reprogramming has long been regarded as a hallmark of cancer, through which cancer cells switch from oxidative phosphorylation to glycolysis for ATP production even in microenvironments with sufficient oxygen (1, 2). To accommodate the challenge of rapid proliferation, cancer cell metabolism is remodeled to increase the biosynthesis of macromolecules including nucleotides, proteins, and lipids as building blocks of new cells (3,4). Although the precise mechanisms underlying this metabolic reprogramming remain elusive, malignant cells often have perturbed metabolism that allows for the accumulation of many metabolic intermediates facilitating the production of cellular building materials (4,5). Numerous studies have demonstrated that the use of glycolysis and the tricarboxylic acid (TCA) 2 cycle intermediates for biosynthesis is a key feature of altered metabolism in cancer cells (6, 7). Among others, citrate, an intermediate metabolite located at the crossroads of glucose metabolism and energy production, is an important sensor of energy homeostasis (8).Accumulating evidence suggests that citrate is involved in both physiological and pathophysiological processes including histone acetylation, insulin secretion, inflammation, ca...

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Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)

Cited by 39 publications

References 39 publications

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

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

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

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