mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis

Selen, Ebru Selin; Wolfgang, Michael J.

doi:10.1016/j.jbc.2021.100884

Cited by 11 publications

(6 citation statements)

References 28 publications

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“…At the peak, S6 phosphorylation was comparable between fed and unfed states. Thus, the induction of mTORC1 was not sufficient to suppress blood βOHB, which is in agreement with the results from reference ( 45 ) and suggests that additional mechanisms must be involved in the regulation of βOHB rhythms.…”

Section: Resultssupporting

confidence: 91%

Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network

Mezhnina

Ebeigbe

Velingkaar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting–based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock–deficient Cry1,2 −/− mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.

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Section: Resultssupporting

confidence: 91%

Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network

Mezhnina

Ebeigbe

Velingkaar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally, under ketogenic conditions, liver morphology and ketone levels in mice lacking hepatocyte p110α do not differ from those of control mice, contrasting the idea that defective p110α signaling is associated with altered FFA uptake by hepatocytes (Chattopadhyay et al, 2011). Thus, in accordance with our previous observations from the lab and others, these results support the notion that autonomous regulation of PPARα activity through the insulin/PI3K/Akt/mTORC1/S6K pathway is minimal in comparison to the induction via adipose tissue lipolysis during fasting periods (Fougerat et al, 2022; Montagner et al, 2016; Régnier et al, 2018; Selen and Wolfgang, 2021).…”

Section: Discussionsupporting

confidence: 92%

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Régnier,

Polizzi,

Fougeray

et al. 2024

Preprint

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Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression. The absence of hepatocyte PI3Kα signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, inad libitumfeeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Therefore, this study highlights the specific role of membrane signaling dependent on hepatocyte PI3Kα in the control of liver gene expression in physiology and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD).HighlightsHepatocyte p110α is required for liver growth, glucose homeostasis, and regulation of liver gene expression.Hepatocyte p110α is dispensable for the regulation of carbohydrate sensing by ChREBP and fatty acid sensing by PPARα.Hepatocyte p110α-mediated regulation of gene expression is related to both insulin receptor-dependent and -independent pathways.Hepatocyte p110α is required for lipid homeostasis and the rewiring of gene expression that occurs during diet-induced obesity.

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“…7K ). Noteworthy, previous studies directly tested whether enhanced mTORC1 activity in the liver (i.e., in parenchymal and non-parenchymal cells) 10 , 16 or specifically in hepatocytes 58 is sufficient for suppressing ketogenesis in a physiological context (i.e. following prolonged fasting).…”

Section: Discussionmentioning

confidence: 99%

“…following prolonged fasting). Interestingly, while enhanced mTORC1 activity in the liver is able to suppress fasting-induced ketogenesis its overactivity only in hepatocytes failed to achieve this effect 10 , 16 , 58 . Our assessment of the results from the aforementioned three studies in combination with our data shown herein would shift the focus from the ketogenic-suppressing role of mTORC1 in hepatocytes (as previously thought and debated) 58 to mTORC1 in non-parenchymal hepatic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, while enhanced mTORC1 activity in the liver is able to suppress fasting-induced ketogenesis its overactivity only in hepatocytes failed to achieve this effect 10 , 16 , 58 . Our assessment of the results from the aforementioned three studies in combination with our data shown herein would shift the focus from the ketogenic-suppressing role of mTORC1 in hepatocytes (as previously thought and debated) 58 to mTORC1 in non-parenchymal hepatic cells. Although the precise identity of which non-parenchymal hepatic cell type(s) mTORC1 (and TLR4) are mediating changes in hepatocyte ketogenesis remain to be elucidated our results will spur new studies aimed at identifying in which and how these yet-to-be-identified mTORC1-expressing cells communicate to hepatocytes to regulate ketogenesis in health (e.g., following prolonged fasting) and disease (e.g., ID).…”

Section: Discussionmentioning

confidence: 99%

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Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

et al. 2022

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Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

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mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis

Cited by 11 publications

References 28 publications

Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network

Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

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