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

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 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.

Genetic determinants of gut microbiota composition and bile acid profiles in mice

“…We identified the positional candidate gene Slc13a5 (S3H Fig), which is a sodium-dependent transporter that mediates cellular uptake of citrate, an important precursor in the biosynthesis of fatty acids and cholesterol (54). Recent evidence indicates that Slc13a5 influences host metabolism and energy homeostasis (55–57). Slc13a5 is a transcriptional target of pregnane X receptor (PXR) (58), which also regulates the expression of genes involved in the biosynthesis, transport, and metabolism of BAs (59).…”

KD-64 – a new selective A2Aadenosine receptor antagonist has anti-inflammatory activity but contrary to the non-selective antagonist – caffeine does not reduce diet-induced obesity in mice

“…This indicates an improvement in glucose tolerance in KD-64-treated mice compared to the obese control mice which might be connected to the anti-inflammatory effect of the tested compound and a decrease in plasma IL-6 levels, since IL-6 and its signalling path play complex roles in metabolic disorders [72]. It was recently reported that IL-6 enhances fatty acid synthesis in murine hepatocytes via the induction of the citrate transporter mIndy [73] and it also exacerbates hepatic inflammation and steatosis [74]. Additionally, adenosine has been shown to promote IL-6 production [75] and our study demonstrates that adenosine A 2A receptor may be associated with this activity, because selective antagonist of this particular receptor decreased IL-6 level in plasma.…”

Hepatitis B reactivation in chronic hepatitis C patients treated with interferon or pan‐oral direct‐acting antivirals

“…(1) We were well aware of the difference in the definition of hepatitis B virus (HBV) reactivation (HBVr) across the studies. However, due to the limited data reported in the included studies, we were unable to use a standardized definition, HBV replication 2 log increase from baseline levels, or a new appearance of HBV DNA to a level of 100 IU/mL (2) to adjust the pooled results.…”