mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion

Quinn, William J.; Wan, Min; Shewale, Swapnil V.; Gelfer, Rebecca; Rader, Daniel J.; Birnbaum, Morris J.; Titchenell, Paul M.

doi:10.1172/jci96036

Cited by 82 publications

(71 citation statements)

References 45 publications

(54 reference statements)

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“…Long-chain polyunsaturated phosphatidylcholines, diacylglycerols, and phosphatidylethanolamine species were identified as key lipid classes contributing to the observed clustering (Figures 4E–4H). These experiments were consistent with the notion that key enzymes of PC, PE, and VLDL synthesis are targets of both mTOR and Xbp1 regulation (Quinn et al, 2017; Sriburi et al, 2004; Wang et al, 2012) and had been detected as being posttranslationally modified in the phospho-proteomic screen described above.…”

Section: Resultssupporting

confidence: 86%

“…Given that hepatic mTOR signaling and Xbp1 splicing are linked to hepatic lipid metabolism (Lee et al, 2008; Li et al, 2010; Quinn et al, 2017), we also compared the effect of refeeding and food perception on hepatic lipid profiles. Untargeted lipidomic profiling on liver tissue of mice that were fasted, exposed to caged food, or refed for 30, 60, 120, or 240 min revealed that the dominant lipid classes detected were phosphatidylcholines, triacylglycerols, phosphatidylethanolamines, and diacylglycer-ols (Figures 4A–4C; Table S3).…”

Section: Resultsmentioning

confidence: 99%

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Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Brandt

Nolte

Henschke

et al. 2018

Cell

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SUMMARY Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas lack of MC4R expression attenuates these responses to sensory food perception. Chemoge-netic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s axis.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Brandt

Nolte

Henschke

et al. 2018

Cell

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“…We observed a concomitant decrease in CTL1 protein expression that was driven by Slc44a1 mRNA translational repression. Although it has been shown that mechanistic target of rapamycin complex 1 is able to control hepatic PC levels through translational regulation of CCTα, (46) CTL1 was not examined. Moreover, while the observed reduction in both CTL1 protein content and functional choline transport in vivo remains correlative, understanding the specific translational control of choline and lipid metabolism genes and the importance of CTL1 to hepatic phospholipid metabolism during obesity remain relevant future questions.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity

et al. 2020

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Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate-choline or the phosphatidylethanolamine N-methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet-induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity-induced hepatic steatosis, male mice fed a 60% high-fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter-like 1 (CTL1) in the liver of mice fed a high-fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity-induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis. (Hepatology Communications 2020;4:876-889).

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“…Postprandial activation of hepatic mTORC1 promotes VLDL-TG secretion by stimulating phosphocholine cytidylyltransferase α (CCTα) activity, the rate-limiting step in the synthesis of phosphatidylcholines (PCs), which are used as the amphipathic molecules that stabilize the TG core of VLDL. (28) In this connection, in cultured mouse hepatocytes under nutrient restriction, changes in PC composition of cellular membranes lead to the formation of Them2/PC-TP complex, which directly suppresses mTORC1 signaling by interacting with tuberous sclerosis complex 2 (TSC2) to stabilize the TSC1-TSC2 complex. (6) However, when FAs are abundant, the Them2/PC-TP complex functions to promote the synthesis of PC for ER membranes.…”

Section: Discussionmentioning

confidence: 99%

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

Auger

Acuña

et al. 2019

Hepatology

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In nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate within the liver because the rates of fatty acid accrual by uptake from plasma and de novo synthesis exceed elimination by mitochondrial oxidation and secretion as very low‐density lipoprotein (VLDL) triglycerides. Thioesterase superfamily member 2 (Them2) is an acyl‐coenzyme A (CoA) thioesterase that catalyzes the hydrolysis of fatty acyl‐CoAs into free fatty acids plus CoASH. Them2 is highly expressed in the liver, as well as other oxidative tissues. Mice globally lacking Them2 are resistant to diet‐induced obesity and hepatic steatosis, and exhibit improved glucose homeostasis. These phenotypes are attributable, at least in part, to roles of Them2 in the suppression of thermogenesis in brown adipose tissue and insulin signaling in skeletal muscle. To elucidate the hepatic function of Them2, we created mice with liver‐specific deletion of Them2 (L‐Them2‐/‐). Although L‐Them2‐/‐ mice were not protected against excess weight gain, hepatic steatosis or glucose intolerance, they exhibited marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These were attributable to reduced rates of VLDL secretion owing to decreased incorporation of plasma‐derived fatty acids into triglycerides. The absence of hepatic steatosis in L‐Them2‐/‐ mice fed chow was explained by compensatory increases in rates of fatty acid oxidation and by decreased de novo lipogenesis in high fat–fed mice. Consistent with a role for Them2 in hepatic VLDL secretion, THEM2 levels were increased in livers of obese patients with NAFLD characterized by simple steatosis. Conclusion: Them2 functions in the liver to direct fatty acids toward triglyceride synthesis for incorporation into VLDL particles. When taken together with its functions in brown adipose and muscle, these findings suggest that Them2 is a target for the management of NAFLD and dyslipidemia.

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mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion

Abstract: Conflict of interest: M. Wan is currently an employee of Agios Pharmaceuticals. M.J. Birnbaum is an employee of Pfizer Inc. P.M. Titchenell receives research funding from Pfizer Inc.

Cited by 82 publications

References 45 publications

Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

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