bims-meprid 2023-11-26 papers

Hepatology. 2023 Nov 20.

Nuclear acly protects liver from ischemia-reperfusion injury.

Wenbin Gao, Liping Zhang, Ziru Li, Tong Wu, Chunhui Lang, Michael W Mulholland, Weizhen Zhang.

BACKGROUND AIMS: Hepatic ischemia-reperfusion (IR) injury is the most common complication that occurs in liver surgery and hemorrhagic shock. ATP citrate lyase (Acly) plays a pivotal role in chromatin modification via generating acetyl-CoA for histone acetylation to influence biological processes. We aim to examine the roles of Acly, which is highly expressed in hepatocytes, in liver IR injury.
APPROACH: The functions of Acly in hepatic IR injury were examined in the mouse model with hepatocytes-specific knockout of Acly. The Acly target genes were analyzed by CUT&RUN assay and RNA Seq. The relationship between the susceptibility of steatotic liver to IR and Acly was determined by gain of function studies in mice.
RESULTS: Hepatic deficiency of Acly exacerbated liver IR injury. IR induced Acly nuclear translocation in hepatocytes, which spatially fueled nuclear acetyl-CoA (AcCoA). This alteration was associated with enhanced acetylation of H3K9 and subsequent activation of Foxa2 signaling pathway. Nuclear localization of Acly enabled Foxa2-mediated protective effects after hypoxia-reperfusion (HR) in cultured hepatocytes, while cytosolic Acly demonstrated no effect. The presence of steatosis disrupted Acly nuclear translocation. In steatotic liver, restoration of Acly nuclear localization through over-expression of Rspondin-1 or Rspondin-3 ameliorated the IR-induced injury.
CONCLUSION: Our results indicate that Acly regulates histone modification via nuclear AcCoA production in hepatic IR. Disruption of Acly nuclear translocation increases the vulnerability of steatotic liver to IR. Nuclear Acly thus may serve as a potential therapeutic target for future interventions in hepatic IR injury, particularly in the context of steatosis.

DOI: https://doi.org/10.1097/HEP.0000000000000692

J Physiol Biochem. 2023 Nov 24.

Diet-inducing hypercholesterolemia show decreased O-GlcNAcylation of liver proteins through modulation of AMPK.

Sanjana Jagannath, Smitha Honnalagere Mallanna, C D Nandini.

O-GlcNAcylation, a nutritionally driven, post-translational modification of proteins, is gaining importance because of its health implications. Changes in O-GlcNAcylation are observed in various disease conditions. Changes in O-GlcNAcylation by diet that causes hypercholesterolemia are not critically looked into in the liver. To address it, both in vitro and in vivo approaches were employed. Hypercholesterolemia was induced individually by feeding cholesterol (H)/high-fat (HF) diet. Global O-GlcNAcylation levels and modulation of AMPK activation in both preventive and curative approaches were looked into. Diet-induced hypercholesterolemia resulted in decreased O-GlcNAcylation of liver proteins which was associated with decreased O-linked N-acetylglucosaminyltransferase (OGT) and Glutamine fructose-6-phosphate amidotransferase-1 (GFAT1). Activation of AMPK by metformin in preventive mode restored the O-GlcNAcylation levels; however, metformin treatment of HepG2 cells in curative mode restored O-GlcNAcylation levels in HF but failed to in H condition (at 24 h). Further, maternal faulty diet resulted in decreased O-GlcNAcylation in pup liver despite feeding normal diet till adulthood. A faulty diet modulates global O-GlcNAcylation of liver proteins which is accompanied by decreased AMPK activation which could exacerbate metabolic syndromes through fat accumulation in the liver.

Keywords: AMPK; Hexosamine biosynthetic pathway; Hypercholesterolemia; Metabolic disease; O-GlcNAcylation

DOI: https://doi.org/10.1007/s13105-023-00997-7

bioRxiv. 2023 Nov 07. pii: 2023.11.07.566074. [Epub ahead of print]

Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production.

Angelo Y Meliton, Rengül Cetin-Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Kun Woo D Shin, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Alexander Muir, Gökhan M Mutlu, Robert B Hamanaka.

A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4- dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO 2 . It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo . Here, we demonstrate that TGF-β induces the expression of MTHFD2 , MTHFD1L , and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production. Combined knockdown of both MTHFD1L and ALDH1L2 also inhibited glycine accumulation and collagen protein production downstream of TGF-β; however knockdown of either protein alone had no inhibitory effect, suggesting that lung fibroblasts can utilize either enzyme to regenerate THF. Pharmacologic inhibition of MTHFD2 recapitulated the effects of MTHFD2 knockdown in lung fibroblasts and ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo . Our results provide insight into the metabolic requirements of lung fibroblasts and provide support for continued development of MTHFD2 inhibitors for the treatment of IPF and other fibrotic diseases.

DOI: https://doi.org/10.1101/2023.11.07.566074

Nature. 2023 Nov 22.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

DOI: https://doi.org/10.1038/s41586-023-06749-3

bioRxiv. 2023 Nov 08. pii: 2023.11.06.565895. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Megan D Radyk, Barbara S Nelson, Christopher J Halbrook, Alexander Wood, Brooke Lavoie, Lucie Salvatore, Gabriel Corfas, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.

Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.

DOI: https://doi.org/10.1101/2023.11.06.565895

Cancer Discov. 2023 Nov 22. OF1

Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.

Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-185