Dataset Information

MTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.

ABSTRACT: Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis. In murine models, the absence of hepatic mTORC1 reduced circulating TAG, despite hepatosteatosis, while activation of mTORC1 depleted liver TAG stores. Additionally, mTORC1 promoted TAG secretion by regulating phosphocholine cytidylyltransferase ? (CCT?), the rate-limiting enzyme involved in the synthesis of phosphatidylcholine (PC). Increasing PC synthesis in mice lacking mTORC1 rescued hepatosteatosis and restored TAG secretion. These data identify mTORC1 as a major regulator of phospholipid biosynthesis and subsequent VLDL-TAG secretion, leading to increased postprandial TAG secretion.

SUBMITTER: Quinn WJ

PROVIDER: S-EPMC5663357 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.

Quinn William J WJ Wan Min M Shewale Swapnil V SV Gelfer Rebecca R Rader Daniel J DJ Birnbaum Morris J MJ Titchenell Paul M PM

The Journal of clinical investigation 20171016 11

Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, ...[more]

PMID: 29035283

Similar Datasets

Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

Project description:BackgroundThe signaling pathways imposing hormonal control over adipocyte differentiation are poorly understood. While insulin and Akt signaling have been found previously to be essential for adipogenesis, the relative importance of their many downstream branches have not been defined. One direct substrate that is inhibited by Akt-mediated phosphorylation is the tuberous sclerosis complex 2 (TSC2) protein, which associates with TSC1 and acts as a critical negative regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Loss of function of the TSC1-TSC2 complex results in constitutive mTORC1 signaling and, through mTORC1-dependent feedback mechanisms and loss of mTORC2 activity, leads to a concomitant block of Akt signaling to its other downstream targets.Methodology/principal findingsWe find that, despite severe insulin resistance and the absence of Akt signaling, TSC2-deficient mouse embryo fibroblasts and 3T3-L1 pre-adipocytes display enhanced adipocyte differentiation that is dependent on the elevated mTORC1 activity in these cells. Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis. Finally, renal angiomyolipomas from patients with tuberous sclerosis complex contain both adipose and smooth muscle-like components with activated mTORC1 signaling and elevated PPARgamma expression.Conclusions/significanceThis study demonstrates that activation of mTORC1 signaling is a critical step in adipocyte differentiation and identifies TSC2 as a primary target of Akt driving this process. Therefore, the TSC1-TSC2 complex regulates the differentiation of mesenchymal cell lineages, at least in part, through its control of mTORC1 activity and PPARgamma expression.

Project description:The Pseudomonas aeruginosa type III secretion system (T3SS) is a primary virulence factor important for phagocytic avoidance, disruption of host cell signaling, and host cell cytotoxicity. ExsA is the master regulator of T3SS transcription. The expression, synthesis, and activity of ExsA is tightly regulated by both intrinsic and extrinsic factors. Intrinsic regulation consists of the well-characterized ExsECDA partner-switching cascade, while extrinsic factors include global regulators that alter exsA transcription and/or translation. To identify novel extrinsic regulators of ExsA, we conducted a transposon mutagenesis screen in the absence of intrinsic control. Transposon disruptions within gene PA2840, which encodes a homolog of the Escherichia coli RNA-helicase DeaD, significantly reduced T3SS gene expression. Recent studies indicate that E. coli DeaD can promote translation by relieving inhibitory secondary structures within target mRNAs. We report here that PA2840, renamed DeaD, stimulates ExsA synthesis at the posttranscriptional level. Genetic experiments demonstrate that the activity of an exsA translational fusion is reduced in a deaD mutant. In addition, exsA expression in trans fails to restore T3SS gene expression in a deaD mutant. We hypothesized that DeaD relaxes mRNA secondary structure to promote exsA translation and found that altering the mRNA sequence of exsA or the native exsA Shine-Dalgarno sequence relieved the requirement for DeaD in vivo. Finally, we show that purified DeaD promotes ExsA synthesis using in vitro translation assays. Together, these data reveal a novel regulatory mechanism for P. aeruginosa DeaD and add to the complexity of global regulation of T3SS.Although members of the DEAD box family of RNA helicases are appreciated for their roles in mRNA degradation and ribosome biogenesis, an additional role in gene regulation is now emerging in bacteria. By relaxing secondary structures in mRNAs, DEAD box helicases are now thought to promote translation by enhancing ribosomal recruitment. We identify here an RNA helicase that plays a critical role in promoting ExsA synthesis, the central regulator of the Pseudomonas aeruginosa type III secretion system, and provide additional evidence that DEAD box helicases directly stimulate translation of target genes. The finding that DeaD stimulates exsA translation adds to a growing list of transcriptional and posttranscriptional regulatory mechanisms that control type III gene expression.

Dataset Information

MTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.

Publications

mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets