bims-medebr 2023-10-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒10‒08
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Deuterium metabolic imaging for 3D mapping of glucose metabolism in humans with central nervous system lesions at 3T.
Depleting glioblastoma cells of very long-chain acyl-CoA synthetase 3 (ACSVL3) produces metabolic alterations in non-lipid pathways.
Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.
Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation.
ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes.
Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis.
RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities.
Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.
The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.
Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.
The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging.
Acetylation-dependent coupling between G6PD activity and apoptotic signaling.
Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice.

Magn Reson Med. 2023 Oct 05.

Deuterium metabolic imaging for 3D mapping of glucose metabolism in humans with central nervous system lesions at 3T.

Philip M Adamson, Keshav Datta, Ron Watkins, Lawrence D Recht, Ralph E Hurd, Daniel M Spielman.

  PURPOSE: To explore the potential of 3T deuterium metabolic imaging (DMI) using a birdcage 2 H radiofrequency (RF) coil in both healthy volunteers and patients with central nervous system (CNS) lesions.METHODS: A modified gradient filter, home-built 2 H volume RF coil, and spherical k-space sampling were employed in a three-dimensional chemical shift imaging acquisition to obtain high-quality whole-brain metabolic images of 2 H-labeled water and glucose metabolic products. These images were acquired in a healthy volunteer and three subjects with CNS lesions of varying pathologies. Hardware and pulse sequence experiments were also conducted to improve the signal-to-noise ratio of DMI at 3T.
RESULTS: The ability to quantify local glucose metabolism in correspondence to anatomical landmarks across patients with varying CNS lesions is demonstrated, and increased lactate is observed in one patient with the most active disease.
CONCLUSION: DMI offers the potential to examine metabolic activity in human subjects with CNS lesions with DMI at 3T, promising for the potential of the future clinical translation of this metabolic imaging technique.

Keywords:  3 Tesla (3T); brain energy metabolism; central nervous system lesions; deuterium metabolic imaging (DMI); glucose metabolism; human brain

DOI:  https://doi.org/10.1002/mrm.29830
bioRxiv. 2023 Sep 18. pii: 2023.09.18.558236. [Epub ahead of print]

Depleting glioblastoma cells of very long-chain acyl-CoA synthetase 3 (ACSVL3) produces metabolic alterations in non-lipid pathways.

Elizabeth A Kolar, Xiaohai Shi, Emily M Clay, Yanqiu Liu, Shuli Xia, Cissy Zhang, Anne Le, Paul A Watkins.

Knockout (KO) of the fatty acid-activation enzyme very long-chain acyl-CoA synthetase 3 (ACSVL3; SLC27A3) in U87MG glioblastoma cells reduced their malignant growth properties both in vitro and in xenografts. These U87-KO glioma cells grew at a slower rate, became adherence-dependent, and were less invasive than parental U87 cells. U87-KO cells produced fewer, slower-growing subcutaneous and intracranial tumors when implanted in NOD-SCID mice. Thus, depleting U87MG cells of ACSVL3 restored these cells to a phenotype more like that of normal astrocytes. To understand the mechanisms underlying these beneficial changes, we investigated several possibilities, including the effects of ACSVL3 depletion on carbohydrate metabolism. Proteomic and metabolomic profiling indicated that ACSVL3 KO produced changes in glucose and energy metabolism. Even though protein levels of glucose transporters GLUT1 and GLUT3 were reduced by KO, cellular uptake of labeled 2-deoxyglucose was unaffected. Glucose oxidation to CO 2 was reduced nearly 7-fold by ACSVL3 depletion, and the cellular glucose level was 25% higher in KO cells. Glycolytic enzymes were upregulated by KO, but metabolic intermediates were essentially unchanged. Surprisingly, lactate production and the levels of lactate dehydrogenase isozymes LDHA and LDHB were elevated by ACSVL3 KO. The activity of the pentose phosphate pathway was found to be lower in KO cells. Citric acid cycle enzymes, electron transport chain complexes, and ATP synthase protein levels were all reduced by ACSVL3 depletion. Mitochondria were elongated in KO cells, but had a more punctate morphology in U87 cells. The mitochondrial potential was unaffected by lack of ACSVL3. We conclude that the beneficial effects of ACSVL3 depletion in human glioblastoma cells may result in part from alterations in diverse metabolic processes that are not directly related to role(s) of this enzyme in fatty acid and/or lipid metabolism. (Supported by NIH 5R01NS062043 and KKI institutional funds.).

DOI: https://doi.org/10.1101/2023.09.18.558236
Nat Metab. 2023 Oct 05.

Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.

Anne Miller, Elisa M York, Sylwia A Stopka, Juan Ramón Martínez-François, Md Amin Hossain, Gerard Baquer, Michael S Regan, Nathalie Y R Agar, Gary Yellen.

Neuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices, coupled with fast metabolite preservation and followed by mass spectrometry (MS) imaging, to generate spatially resolved metabolomics and isotope-tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs. Increased glucose metabolism in response to stimulation is accompanied by mobilization of endogenous inosine into pentose phosphates via the action of purine nucleotide phosphorylase (PNP). The PNP reaction is an integral part of the neuronal response to stimulation, because inhibition of PNP leaves DGCs energetically impaired during recovery from strong activation. Performing MS imaging on brain slices bridges the gap between live-cell physiology and the deep chemical analysis enabled by MS.

DOI: https://doi.org/10.1038/s42255-023-00890-z
Mol Psychiatry. 2023 Oct 04.

Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation.

Philip D Campbell, Isaiah Lee, Summer Thyme, Michael Granato.

Microdeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes, mrpl40 and prodha, encode for mitochondrial proteins and, similar to what we observed in mrpl40 and prodha mutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Single mutant analysis shows that both mrpl40 and prodha mutants display aberrant neural stem and progenitor cell proliferation, with each gene regulating distinct cell populations. Finally, double mutants for both mrpl40 and prodha display aggravated behavioral phenotypes and neural stem and progenitor cell analysis reveals a previously unrecognized partially redundant role for mrpl40 and prodha in regulating radial glia-like cell proliferation. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.

DOI: https://doi.org/10.1038/s41380-023-02272-z
Cell Rep. 2023 Sep 29. pii: S2211-1247(23)01195-6. [Epub ahead of print]42(10): 113183

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes.

Hyein Lee, Sukhee Cho, Mi-Jin Kim, Yeo Jin Park, Eunji Cho, Yeon Suk Jo, Yong-Seok Kim, Jung Yi Lee, Themis Thoudam, Seung-Hwa Woo, Se-In Lee, Juyeong Jeon, Young-Sam Lee, Byung-Chang Suh, Jong Hyuk Yoon, Younghoon Go, In-Kyu Lee, Jinsoo Seo.

  Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

Keywords:  ApoE4; CP: Cell biology; CP: Metabolism; glucose metabolism; human astrocytes; lysosomal cholesterol accumulation; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2023.113183
J Cell Biol. 2023 Dec 04. pii: e202308055. [Epub ahead of print]222(12):

Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis.

Yeongho Kim, Grace Mavodza, Can E Senkal, Christopher G Burd.

Sphingomyelin plays a key role in cellular cholesterol homeostasis by binding to and sequestering cholesterol in the plasma membrane. We discovered that synthesis of very long chain (VLC) sphingomyelins is inversely regulated by cellular cholesterol levels; acute cholesterol depletion elicited a rapid induction of VLC-sphingolipid synthesis, increased trafficking to the Golgi apparatus and plasma membrane, while cholesterol loading reduced VLC-sphingolipid synthesis. This sphingolipid-cholesterol metabolic axis is distinct from the sterol responsive element binding protein pathway as it requires ceramide synthase 2 (CerS2) activity, epidermal growth factor receptor signaling, and was unaffected by inhibition of protein translation. Depletion of VLC-ceramides reduced plasma membrane cholesterol content, reduced plasma membrane lipid packing, and unexpectedly resulted in the accumulation of cholesterol in the cytoplasmic leaflet of the lysosome membrane. This study establishes the existence of a cholesterol-sphingolipid regulatory axis that maintains plasma membrane lipid homeostasis via regulation of sphingomyelin synthesis and trafficking.

DOI: https://doi.org/10.1083/jcb.202308055
Heliyon. 2023 Oct;9(10): e20384

RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities.

Lei Wu, Fang Wang, Carole L Moncman, Mritunjay Pandey, Harrison A Clarke, Hilaree N Frazier, Lyndsay E A Young, Matthew S Gentry, Weikang Cai, Olivier Thibault, Ramon C Sun, Douglas A Andres.

  Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

Keywords:  Endothelin-1; Lipidomics; MALDI-MSI; Myelin; Myelination; Oligodendrocyte progenitor cell; Ras; Rit GTPase

DOI:  https://doi.org/10.1016/j.heliyon.2023.e20384
Neurotrauma Rep. 2023 ;4(1): 643-654

Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.

Aurore Nkiliza, Claire J C Huguenard, Gregory J Aldrich, Scott Ferguson, Adam Cseresznye, Teresa Darcey, James E Evans, Michael Dretsch, Michael Mullan, Fiona Crawford, Laila Abdullah.

  Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control = 52, mTBI = 21, PTSD = 34, and TBI + PTSD = 13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.

Keywords:  apolipoprotein E (APOE); arachidonic acid (AA); ethanolamides; mild TBI; oxylipins

DOI:  https://doi.org/10.1089/neur.2023.0045
Front Mol Neurosci. 2023 ;16 1209703

The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.

Honglu Yu, Min Xiong, Zhentao Zhang.

  Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3β and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; protein aggregation

DOI:  https://doi.org/10.3389/fnmol.2023.1209703
J Neurochem. 2023 Sep 30.

Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.

Elizabeth Smith Khoury, Ruchit V Patel, Caroline O'Ferrall, Amanda Fowler, Nirnath Sah, Anjali Sharma, Siddharth Gupta, Susanna Scafidi, Joshua S Kurtz, Sarah J Olmstead, Sapna R Kudchadkar, Rangaramanujam M Kannan, Mary E Blue, Sujatha Kannan.

  Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.

Keywords:  epilepsy; glial dysfunction; microglia targeting; nanomedicine, neurodevelopmental disorders; preclinical studies; sleep dysfunction

DOI:  https://doi.org/10.1111/jnc.15960
Nat Commun. 2023 Oct 06. 14(1): 6254

The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging.

Xiaowei Sun, Jie Shen, Norbert Perrimon, Xue Kong, Dan Wang.

While disorders in lipid metabolism have been associated with aging and age-related diseases, how lipid metabolism is regulated during aging is poorly understood. Here, we characterize the Drosophila endoribonuclease CG2145, an ortholog of mammalian EndoU that we named Age-related lipid regulator (Arlr), as a regulator of lipid homeostasis during aging. In adult adipose tissues, Arlr is necessary for maintenance of lipid storage in lipid droplets (LDs) as flies age, a phenotype that can be rescued by either high-fat or high-glucose diet. Interestingly, RNA-seq of arlr mutant adipose tissues and RIP-seq suggest that Arlr affects lipid metabolism through the degradation of the mRNAs of lipolysis genes - a model further supported by the observation that knockdown of Lsd-1, regucalcin, yip2 or CG5162, which encode genes involved in lipolysis, rescue the LD defects of arlr mutants. In addition, we characterize DendoU as a functional paralog of Arlr and show that human ENDOU can rescue arlr mutants. Altogether, our study reveals a role of ENDOU-like endonucleases as negative regulator of lipolysis.

DOI: https://doi.org/10.1038/s41467-023-42042-7
Nat Commun. 2023 Oct 05. 14(1): 6208

Acetylation-dependent coupling between G6PD activity and apoptotic signaling.

Fang Wu, Natali H Muskat, Inbar Dvilansky, Omri Koren, Anat Shahar, Roi Gazit, Natalie Elia, Eyal Arbely.

Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to understanding how metabolic cues mediate metabolic enzyme regulation and cellular signaling. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is acetylated on multiple lysine residues. Using site-specifically acetylated G6PD, we show that acetylation can activate (AcK89) and inhibit (AcK403) G6PD. Acetylation-dependent inactivation is explained by structural studies showing distortion of the dimeric structure and active site of G6PD. We provide evidence for acetylation-dependent K95/97 ubiquitylation of G6PD and Y503 phosphorylation, as well as interaction with p53 and induction of early apoptotic events. Notably, we found that the acetylation of a single lysine residue coordinates diverse acetylation-dependent processes. Our data provide an example of the complex roles of acetylation as a posttranslational modification that orchestrates the regulation of enzymatic activity, posttranslational modifications, and apoptotic signaling.

DOI: https://doi.org/10.1038/s41467-023-41895-2
Mol Metab. 2023 Oct 03. pii: S2212-8778(23)00149-7. [Epub ahead of print] 101815

Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice.

Mikala M Zelows, Corissa Cady, Nikitha Dharanipragada, Anna E Mead, Zachary A Kipp, Evelyn A Bates, Venkateshwari Varadharajan, Rakhee Banerjee, Se-Hyung Park, Nathan R Shelman, Harrison A Clarke, Tara R Hawkinson, Terrymar Medina, Ramon C Sun, Todd A Lydic, Terry D Hinds, J Mark Brown, Samir Softic, Gregory A Graf, Robert N Helsley.

  BACKGROUND AND AIMS: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.APPROACH AND RESULTS: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.
CONCLUSIONS: Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

Keywords:  Fatty Acid Metabolism; Lipid Droplets; Lipolysis; Mitochondria; Triglycerides

DOI:  https://doi.org/10.1016/j.molmet.2023.101815