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

Brachs, Sebastian; Winkel, Angelika F.; Tang, Hui; Birkenfeld, Andreas L.; Brunner, Bodo; Jahn‐Hofmann, Kerstin; Margerie, Daniel; Ruetten, Hartmut; Schmoll, Dieter; Spranger, Joachim

doi:10.1016/j.molmet.2016.08.004

Cited by 47 publications

(54 citation statements)

References 44 publications

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“…(48) In line with this mechanism, small interfering RNA-mediated mIndy knockdown reduced total fat content in human hepatocytes. (26) Knockdown of mIndy in rats using antisense oligonucleotides (14) and in mice using small interfering RNA (49) reduced liver fat content when rodents were fed an HFD. Most importantly, inhibition of mINDY using a novel small molecule improved glucose tolerance and ameliorated liver fat content upon high-fat feeding in mice.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Reduction in the analogue gene expression in both fruit flies and worms surprisingly causes an increase of average life span as a result of decreasing body size and fat content [20,26]. Beyond this former discovery, results obtained from mice were in accordance in that suppression of mammalian PMCT contributes to reduction in hepatic lipid accumulation, amelioration of hepatic insulin sensitivity, and prevention of diet-induced nonalcoholic fatty liver disease in high-fat diet-induced mice [27]. Therefore, PMCT plays a role in incorporating citrate for fatty acid synthesis, accumulation of which is rather disadvantageous in normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recent study has also confirmed that citrate transported by mammalian INDY (mINDY) contributes in regulation of liver fat metabolism [27]. Inhibition of mINDY reduced hepatic lipid accumulation, improved hepatic insulin sensitivity, and prevented diet-induced nonalcoholic fatty liver disease in adult C57BL6/J mice [27]. Thus, PMCT has been proposed as a therapeutic target for obesity and diabetes [28].…”

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confidence: 94%

“…A reduction in INDY activity in D. melanogaster and functional knockdown of NAC-2 by RNAi in C. elegans have a similar effect, leading not only to a significant increase in average life span, but also causing a significant decrease in body size and fat content without an alteration of either physical activity or fertility [20,26]. Recent study has also confirmed that citrate transported by mammalian INDY (mINDY) contributes in regulation of liver fat metabolism [27]. Inhibition of mINDY reduced hepatic lipid accumulation, improved hepatic insulin sensitivity, and prevented diet-induced nonalcoholic fatty liver disease in adult C57BL6/J mice [27].…”

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confidence: 99%

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Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

et al. 2018

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Suppression of the expression or activities of enzymes that are involved in the synthesis of de novo lipogenesis ( DNL ) in cancer cells triggers cell death via apoptosis. The plasma membrane citrate transporter ( PMCT ) is the initial step that translocates citrate from blood circulation into the cytoplasm for de novo long‐chain fatty acids synthesis. This study investigated the antitumor effect of the PMCT inhibitor ( PMCT i) in inducing apoptosis by inhibiting the DNL pathway in HepG2 cells. The present findings showed that PMCT i reduced cell viability and enhanced apoptosis through decreased intracellular citrate levels, which consequently caused inhibition of fatty acid and triacylglycerol productions. Thus, as a result of the reduction in fatty acid synthesis, the activity of carnitine palmitoyl transferase‐1 ( CPT ‐1) was suppressed. Decreased CPT ‐1 activity also facilitated the disruption of mitochondrial membrane potential (ΔΨm) leading to stimulation of apoptosis. Surprisingly, primary human hepatocytes were not affected by PMCT i. Increased caspase‐8 activity as a consequence of reduction in fatty acid synthesis was also found to cause disruption of ΔΨm. In addition, apoptosis induction by PMCT i was associated with an enhanced reactive oxygen species generation. Taken together, we suggest that inhibition of the DNL pathway following reduction in citrate levels is an important regulator of apoptosis in HepG2 cells via suppression of CPT ‐1 activity. Thus, targeting the DNL pathway mediating CPT ‐1 activity by PMCT i may be a selective potential anticancer therapy.

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“…Hyperinsulinemic-euglycemic (HE) clamps in conscious, restrained mice and activity and indirect calorimetry (TSE LabMaster System) were performed as described previously (17).…”

Section: Animal Experimentsmentioning

confidence: 99%

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

et al. 2018

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Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide N-methyltransferase (NNMT) in high-fat diet (HFD)–fed mice has been reported to reduce weight gain and plasma insulin levels and to improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout mice (NNMT−/−), we tested the hypothesis that Nnmt deletion protects against diet-induced obesity and its metabolic consequences in males and females on obesity-inducing diets. We also examined samples from a human weight reduction (WR) study for adipose NNMT (aNNMT) expression and plasma 1-methylnicotinamide (MNAM) levels. In Western diet (WD)–fed female mice, NNMT-ASO-KD reduced body weight, fat mass, and insulin level and improved glucose tolerance. Although NNMT−/− mice fed a standard diet had no obvious phenotype, NNMT−/− males fed an HFD showed strongly improved insulin sensitivity (IS). Furthermore, NNMT−/− females fed a WD showed reduced weight gain, less fat, and lower insulin levels. However, no improved glucose tolerance was observed in NNMT−/− mice. Although NNMT expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides aNNMT expression modulate circulating MNAM levels during WR. In summary, upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, we observed sex- and diet-specific differences in body composition, weight, and glucose tolerance and estimates of IS.

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

Cited by 47 publications

References 44 publications

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

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

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

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