T266M variants of ANGPTL4 improve lipid metabolism by modifying their binding affinity to acetyl-CoA carboxylase in obstructive sleep apnea.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the ß-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. METHODS: This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured via ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA. RESULTS: Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, p = 6.02 × 10-16). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4. CONCLUSIONS: Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.

ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARα- CPT1A axis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose global prevalence is rapidly increasing. Acetyl CoA carboxylases 1 (ACACA) is the key enzyme that controls the rate of fatty acid synthesis. Hence, it is crucial to investigate the function of ACACA in regulating lipid metabolism during the progress of NAFLD. METHODS: Firstly, a fatty liver mouse model was established by high-fat diet at 2nd, 12th, and 20th week, respectively. Then, transcriptome analysis was performed on liver samples to investigate the underlying mechanisms and identify the target gene of the occurrence and development of NAFLD. Afterwards, lipid accumulation cell model was induced by palmitic acid and oleic acid (PA ∶ OA molar ratio = 1∶2). Next, we silenced the target gene ACACA using small interfering RNAs (siRNAs) or the CMS-121 inhibitor. Subsequently, experiments were performed comprehensively the effects of inhibiting ACACA on mitochondrial function and lipid metabolism, as well as on AMPK- PPARα- CPT1A pathway. RESULTS: This data indicated that the pathways significantly affected by high-fat diet include lipid metabolism and mitochondrial function. Then, we focus on the target gene ACACA. In addition, the in vitro results suggested that inhibiting of ACACA in vitro reduces intracellular lipid accumulation, specifically the content of TG and TC. Furthermore, ACACA ameliorated mitochondrial dysfunction and alleviate oxidative stress, including MMP complete, ATP and ROS production, as well as the expression of mitochondria respiratory chain complex (MRC) and AMPK proteins. Meanwhile, ACACA inhibition enhances lipid metabolism through activation of PPARα/CPT1A, leading to a decrease in intracellular lipid accumulation. CONCLUSION: Targeting ACACA can reduce lipid accumulation by mediating the AMPK- PPARα- CPT1A pathway, which regulates lipid metabolism and alleviates mitochondrial dysfunction.

ND630 controls ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003.

BACKGROUND: ND630 is believed to be a new therapy pharmacologic molecule in targeting the expression of ACACA and regulating the lipid metabolism. However, the function of ND630 in prostate cancer remains unknown. KIF18B, as an oncogene, plays a vital role in prostate cancer progression. circKIF18B_003 was derived from oncogene KIF18B and was markedly overexpressed in prostate cancer tissues. We speculated that oncoprotein KIF18B-derived circRNA circKIF18B_003 might have roles in prostate cancer promotion. The aim of this study was to validate whether ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. METHODS: RT-qPCR was used to analyze the expression of circKIF18B_003 in prostate cancer cell lines and prostate cancer samples. circKIF18B_003 expression was modulated in prostate cancer cells using circKIF18B_003 interference or overexpression plasmid. We examined the function and effects of circKIF18B_003 in prostate cancer cells using CCK-8, colony formation, wound healing, and Transwell invasion assays and xenograft models. Fluorescence in situ hybridization (FISH) was performed to evaluate the localization of circKIF18B_003. RNA immunoprecipitation (RIP), RNA pull down, and luciferase reporter assay were performed to explore the potential mechanism of circKIF18B_003. RESULTS: The function of ND630 was determined in this study. circKIF18B_003 was overexpressed in prostate cancer tissues, and overexpression of circKIF18B_003 was associated with poor survival outcome of prostate cancer patients. The proliferation, migration, and invasion of prostate cancer cells were enhanced after up-regulation of circKIF18B_003. circKIF18B_003 is mainly located in the cytoplasm of prostate cancer cells, and the RIP and RNA pull down assays confirmed that circKIF18B_003 could act as a sponge for miR-370-3p. Further study demonstrated that up-regulation of circKIF18B_003 increased the expression of ACACA by sponging miR-370-3p. The malignant ability of prostate cancer cells enhanced by overexpression of circKIF18B_003 was reversed by the down-regulation of ACACA. We found that overexpression of circKIF18B_003 was associated with lipid metabolism, and a combination of ND-630 and docetaxel markedly attenuated tumor growth. CONCLUSION: ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. ND630 and circKIF18B_003 may represent a novel target for prostate cancer.

Revisiting two dogmas of conservation science.

Conservation science is a morally motivated field, with implicit and explicit values built into its practice. As such, conservationists must engage with conservation ethics to interrogate underlying values. We examine cutting-edge ecological science and contemporary ethics to revisit two conservation norms that have become dogmatic in the field: ecological collectives, but not individual animals, are valuable and anthropomorphism should be staunchly avoided. Emerging studies demonstrate that individuals and their intraspecific variation can be instrumentally valuable for conservation science, and there is an emerging consensus within environmental philosophy around the moral worth of individuals. Thus, we suggest conservation science should explicitly recognize the value of individuals. We also argue that avoiding anthropomorphism is detrimental to conservation because critical anthropomorphism enables a more nuanced scientific approach-allowing conservationists to ask enlightened questions with creativity and compassion. We provide evidence that both dogmatic norms are scientifically and morally outdated and propose new normative values to push conservation towards more robust science and ethical practice.

Revisión de dos dogmas de las ciencias de la conservación Resumen Las ciencias de la conservación son un campo con motivaciones morales y valores implícitos y explícitos integrados en su práctica. Por lo tanto, los conservacionistas deben trabajar con la ética de la conservación para interrogar los valores subyacentes. Analizamos la ecología de vanguardia y la ética contemporánea para revisar dos normas que se han convertido en dogmas dentro del campo: los colectivos ecológicos, pero no los animales individuales, son valiosos y el antropomorfismo debe evitarse a toda costa. Los estudios emergentes demuestran que los individuos y sus variaciones intraespecíficas pueden tener un valor instrumental para las ciencias de la conservación y que existe un consenso emergente dentro de la filosofía ambiental en torno al valor moral de los individuos. Por lo tanto, sugerimos que las ciencias de la conservación deberían reconocer de forma explícita el valor de los individuos. También discutimos que evitar el antropomorfismo daña a la conservación pues el antropomorfismo crítico permite una estrategia científica más matizada-lo que permite que los conservacionistas hagan preguntas informadas con creatividad y compasión. Proporcionamos evidencias de que ambos dogmas son científica y moralmente obsoletos y proponemos nuevos valores normativos para guiar a la conservación hacia una ciencia más sólida y una práctica más ética.

DC: 0-5 system in clinical assessment with specialty pediatric populations.

Early childhood mental health (ECMH) programs provide an opportunity to provide specialized mental health services to vulnerable young children and connect them with necessary evidence-based early intervention. However, there is a paucity of descriptive and explorative studies of the clinic protocols in the literature. Even within published work, there is a lack of standardization in clinical models and diagnostic systems limiting comparison and extrapolation. This paper describes how the DC: 0-5 framework guides the development of the model for an ECMH clinic embedded in the context of academic pediatrics. It also highlights the opportunity the DC 0-5 presents for developing the standardized protocols and a mechanism for standardized data collection in clinical settings. The paper demonstrates the utility of using the DC 0-5 in protocol development, assessment and data collection the mental health assessments of 87 children ages 0-6 were reviewed to gather information on history, presenting problems, parent-child relationship, and mental health diagnoses. This paper and associated data underscore the utility and necessity of ECMH clinics while identifying challenges in the field.

Los programas de salud mental en la temprana niñez ofrecen una oportunidad para proveer servicios de salud mental especializados a niños pequeños vulnerables y ponerlos en contacto con la necesaria intervención temprana que se base en la evidencia. Sin embargo, hay escasez de estudios descriptivos y de exploración de los protocolos clínicos en la información impresa. Aun dentro de los trabajos publicados, se da una falta de estandarización en los modelos clínicos y sistemas de diagnóstico, lo cual limita la comparación y la extrapolación. Este ensayo describe cómo el marco de trabajo DC: 0-5 guía el desarrollo del modelo para una clínica de salud mental en la temprana niñez enmarcado dentro del contexto de la pediatría académica. También resalta la oportunidad que DC 0 a 5 presenta para desarrollar los protocolos estandarizados y un mecanismo para la recolección de datos estandarizados en escenarios clínicos. El ensayo demuestra la utilidad de usar el DC 0 a 5 en el desarrollo de protocolos, evaluación y recolección de datos. Se revisaron las evaluaciones de salud mental de 87 niños de edad 0-6 para obtener información acerca del historial, la presentación de problemas, la relación progenitor-niño y la diagnosis de salud mental. Este ensayo y la información asociada subraya la utilidad y necesidad de las clínicas de salud mental en la temprana niñez, al tiempo que identifica los retos en el campo.

Les programmes de santé mentale de la petite enfance offrent une chance d'offrir des services spécialisés de santé mentale à des jeunes enfants vulnérables et de les connecter à une intervention précoce ayant des preuves à l'appui. Cependant, dans les recherches, il existe très peu d'études descriptives et exploratoires des protocoles cliniques. Même au sein du travail qui est publié, nous observons un manque de standardisation dans les modèles cliniques et dans les systèmes diagnostiques, limitant la comparaison et l'extrapolation. Cet article décrit comment la structure DC: 0-5 guide le développement du modèle pour une clinique de santé mentale de la petite enfance ancrée dans le contexte de la pédiatrie académique. L'article met également en lumière l'opportunité que présente la DC 0 à 5 pour le développement de protocoles standardisés et un mécanisme pour une collecte de données standardisée dans des contextes cliniques. Nous démontrons l'utilité de l'utilisation de la DC 0 à 5 dans le développement du protocole, l'évaluation et la collecte de données. Les évaluations de santé mentale de 87 enfants âgés de 0-6 ont été passées en revue afin de récolter des données sur l'histoire, ce qui présente des problèmes, la relation parent-enfant, et les diagnostics de santé mentale. Cet article et les données qui y sont liées soulignent l'utilité et la nécessité des cliniques de santé mentale de la petite enfance tout en identifiant les défis qui se présentent dans ce domaine.

Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials.

Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n = 107; control cohort: FOLFIRI/cetuximab arm, n = 129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n = 163) trials, was genotyped using the OncoArray-500 K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. Findings: In the discovery cohort, patients with FASN rs4485435 any C allele (n = 21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n = 62) in multivariable (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15-3.74; p = 0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p = 0.017) on PFS. Interpretation: Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. Funding: This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review.

Pathogenic variants in ACACA are the cause of acetyl-CoA carboxylase deficiency with an autosomal recessive inheritance that is identified by hypotonia, motor, and intellectual developmental delay. In this article, we describe a seven-year-old boy who is the child of consanguineous parents with a homozygous variant in ACACA (NM_198834.3:c.6641C > A, p.P2214H) that was detected by Whole-Exome Sequencing and confirmed by Sanger sequencing. This is the first reported patient of acetyl-CoA carboxylase deficiency that results from a homozygous pathogenic variant in the ACACA gene in the Iranian family. The proband presents with motor and intellectual developmental delay, muscle weakness, language disorder, facial dysmorphism, and poor growth. The patient discussed here is similar to other patients that were previously published; however, we were able to identify seizure that has hitherto not been reported. This paper describes the third person with a novel variant in the ACACA gene in the world that accounts for acetyl-CoA carboxylase deficiency and implicates the clinical spectrum of the disease. Finally, we describe an individual-based review of the symptoms associated with acetyl-CoA carboxylase deficiency. So far, only two acetyl-CoA carboxylase deficiency patients have been reviewed in the literature.

Animal agency in wildlife conservation and management.

Wildlife conservation and management (WCM) practices have been historically drawn from a wide variety of academic fields, yet practitioners have been slow to engage with emerging conversations about animals as complex beings, whose individuality and sociality influence their relationships with humans. We propose an explicit acknowledgement of wild, nonhuman animals as active participants in WCM. We examined 190 studies of WCM interventions and outcomes to highlight 3 common assumptions that underpin many present approaches to WCM: animal behaviors are rigid and homogeneous; wildlife exhibit idealized wild behavior and prefer pristine habitats; and human-wildlife relationships are of marginal or secondary importance relative to nonhuman interactions. We found that these management interventions insufficiently considered animal learning, decision-making, individuality, sociality, and relationships with humans and led to unanticipated detrimental outcomes. To address these shortcomings, we synthesized theoretical advances in animal behavioral sciences, animal geographies, and animal legal theory that may help conservation professionals reconceptualize animals and their relationships with humans. Based on advances in these fields, we constructed the concept of animal agency, which we define as the ability of animals to actively influence conservation and management outcomes through their adaptive, context-specific, and complex behaviors that are predicated on their sentience, individuality, lived experiences, cognition, sociality, and cultures in ways that shape and reshape shared human-wildlife cultures, spaces, and histories. Conservation practices, such as compassionate conservation, convivial conservation, and ecological justice, incorporate facets of animal agency. Animal agency can be incorporated in conservation problem-solving by assessing the ways in which agency contributes to species' survival and by encouraging more adaptive and collaborative decision-making among human and nonhuman stakeholders.

RESUMEN: Aunque las prácticas de gestión y conservación de fauna (GCF) han partido históricamente de una gama amplia de áreas académicas, los practicantes se han visto lentos para participar en las conversaciones emergentes sobre los animales como seres complejos, cuya individualidad y sociabilidad influyen sobre sus relaciones con los humanos. Proponemos un reconocimiento explícito de los animales no humanos silvestres como participantes activos en la GCF. Para esto, examinamos 190 estudios sobre las intervenciones y los resultados de GCF para resaltar tres supuestos comunes que respaldan a muchas estrategias actuales de GCF: el comportamiento animal es rígido y homogéneo, la fauna exhibe un comportamiento silvestre idealizado y prefiere hábitats prístinos, y las relaciones humano-fauna son de importancia marginal o secundaria en relación con las interacciones no humanas. Descubrimos que estas intervenciones de gestión no consideran lo suficientemente el aprendizaje, toma de decisiones, individualidad, sociabilidad y relaciones con los humanos de los animales, por lo que llevan a resultados imprevistos y perjudiciales. Para lidiar con estas limitaciones, sintetizamos los avances teóricos que han tenido las ciencias dedicadas al comportamiento animal, la geografía animal y la teoría legal animal que pueden ayudar a los profesionales de la conservación a reformular el concepto de animal y sus relaciones con los humanos. Con base en los avances en estas áreas construimos el concepto de agencia animal, el cual definimos como la habilidad que tienen los animales para influir activamente sobre la conservación y los resultados de manejo por medio de su comportamiento adaptativo, complejo y específico al contexto, los cuales están basados en su sensibilidad, individualidad, experiencias vividas, conocimiento, sociabilidad y culturas, de manera que construyen y reconstruyen las culturas, espacios e historias humano-fauna. Las prácticas de conservación, como la conservación compasiva, la conservación acogedora y la justicia ecológica, incorporan facetas de la agencia animal. La agencia animal puede incorporarse en la solución de los problemas de conservación al evaluar las formas en las que la agencia contribuye a la supervivencia de la especie y al alentar una toma de decisiones más adaptativa y colaborativa entre los actores humanos y los no humanos.

Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors.

Tick-borne encephalitis virus (TBEV), the most medically relevant tick-transmitted flavivirus in Eurasia, targets the host central nervous system and frequently causes severe encephalitis. The severity of TBEV-induced neuropathogenesis is highly cell-type specific and the exact mechanism responsible for such differences has not been fully described yet. Thus, we performed a comprehensive analysis of alterations in host poly-(A)/miRNA/lncRNA expression upon TBEV infection in vitro in human primary neurons (high cytopathic effect) and astrocytes (low cytopathic effect). Infection with severe but not mild TBEV strain resulted in a high neuronal death rate. In comparison, infection with either of TBEV strains in human astrocytes did not. Differential expression and splicing analyses with an in silico prediction of miRNA/mRNA/lncRNA/vd-sRNA networks found significant changes in inflammatory and immune response pathways, nervous system development and regulation of mitosis in TBEV Hypr-infected neurons. Candidate mechanisms responsible for the aforementioned phenomena include specific regulation of host mRNA levels via differentially expressed miRNAs/lncRNAs or vd-sRNAs mimicking endogenous miRNAs and virus-driven modulation of host pre-mRNA splicing. We suggest that these factors are responsible for the observed differences in the virulence manifestation of both TBEV strains in different cell lines. This work brings the first complex overview of alterations in the transcriptome of human astrocytes and neurons during the infection by two TBEV strains of different virulence. The resulting data could serve as a starting point for further studies dealing with the mechanism of TBEV-host interactions and the related processes of TBEV pathogenesis.

Biallelic Mutations in ACACA Cause a Disruption in Lipid Homeostasis That Is Associated With Global Developmental Delay, Microcephaly, and Dysmorphic Facial Features.

OBJECTIVE: We proposed that the deficit of ACC1 is the cause of patient symptoms including global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. We evaluated the possible disease-causing role of the ACACA gene in developmental delay and investigated the pathogenesis of ACC1 deficiency. METHODS: A patient who presented with global developmental delay with unknown cause was recruited. Detailed medical records were collected and reviewed. Whole exome sequencing found two variants of ACACA with unknown significance. ACC1 mRNA expression level, protein expression level, and enzyme activity level were detected in patient-derived cells. Lipidomic analysis, and in vitro functional studies including cell proliferation, apoptosis, and the migratory ability of patient-derived cells were evaluated to investigate the possible pathogenic mechanism of ACC1 deficiency. RNAi-induced ACC1 deficiency fibroblasts were established to assess the causative role of ACC1 deficit in cell migratory disability in patient-derived cells. Palmitate supplementation assays were performed to assess the effect of palmitic acid on ACC1 deficiency-induced cell motility deficit. RESULTS: The patient presented with global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. A decreased level of ACC1 and ACC1 enzyme activity were detected in patient-derived lymphocytes. Lipidomic profiles revealed a disruption in the lipid homeostasis of the patient-derived cell lines. In vitro functional studies revealed a deficit of cell motility in patient-derived cells and the phenotype was further recapitulated in ACC1-knockdown (KD) fibroblasts. The cell motility deficit in both patient-derived cells and ACC1-KD were attenuated by palmitate. CONCLUSION: We report an individual with biallelic mutations in ACACA, presenting global development delay. In vitro studies revealed a disruption of lipid homeostasis in patient-derived lymphocytes, further inducing the deficit of cell motility capacity and that the deficiency could be partly attenuated by palmitate.

Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies.

BACKGROUND: Metabolic reprogramming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, tumor cells in lymphoid malignancies often share similar environments and potentially similar metabolic profiles. We examined cells from mouse models of MYC-, RAS-, and BCR-ABL-driven lymphoid malignancies and find a convergence on de novo lipogenesis. We explore the potential role of MYC in mediating lipogenesis by 13C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death both in vitro and in vivo and does not induce cell death of normal splenocytes. METHODS: We analyzed RNA-seq data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models and oncogene-driven human cell lines, we determined gene regulation, metabolic profiles, and sensitivity to inhibition of lipogenesis in lymphoid malignancies. We utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL-, RAS-, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpaired t-tests and one-way ANOVA. RESULTS: This study illustrates that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived from conditional MYC, RAS, and BCR-ABL transgenic murine models, we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(tetradecloxy)-2-furic acid (TOFA), and other lipogenesis inhibitors. We performed metabolic tracing studies to confirm the influence of c-MYC and TOFA on lipogenesis. We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observe delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a metabolic liability due to the general convergence on de novo lipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cells in vivo. CONCLUSIONS: These studies suggest that de novo lipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability. TRIAL REGISTRATION: This study does not include any clinical interventions on human subjects.

A Candidate Gene Association Study for Economically Important Traits in Czech Dairy Goat Breeds.

Milk production is influenced by many factors, including genetic and environmental factors and their interactions. Animal health, especially udder health, is usually evaluated by the number of somatic cells. The present study described the effect of polymorphisms in the ACACA, BTN1A1, LPL, and SCD genes on the daily milk yield, fat, and protein percentages and somatic cell count. In this study, 590 White Shorthaired (WSH) and Brown Shorthaired (BSH) goats were included. SNP genotyping was performed by PCR-RFLP and multiplex PCR followed by SNaPshot minisequencing analysis. The linear mixed model with repeated measurement was used to identify the genetic associations between the studied genes/SNPs and chosen traits. All selected genes were polymorphic in the tested goat populations and showed significant associations with milk traits. Only BTN1A1 (SNP g.599 A > G) showed a significant association with the somatic cell score. After Bonferroni correction, a significant effect of LPL g.300G > A on daily milk yield and fat percentage, LPL g.185G > T on protein percentage, and LPL G50C, SCD EX3_15G > A, and SCD EX3_68A > G on fat percentage was found. The importance of environmental factors, such as the herd-year effect, month of milking, and lactation order on all milk performance indicators was confirmed.

Nano-selenium alleviating the lipid metabolism disorder of LMH cells induced by potassium dichromate via down-regulating ACACA and FASN.

Chromium (Cr) VI is a common environmental contaminant highly toxic to livers. To explore the protective effect of nano-selenium (NANO-Se) on broiler liver damage caused by Cr (VI), this experiment was conducted with chicken hepatocellular carcinoma cell line (LMH) as the research object, using potassium dichromate (PDC) and NANO-Se gel for culturing cells. The results indicated that: (1) in the PDC-exposure group, LMH cells being treated with 20 µmol/L PDC for 24 h, IC50 (median inhibition concentration) = 23.427 could significantly reduce cell activity (p < 0.01) which decreased over time. PDC markedly increased the concentration of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) in LMH cells (p < 0.01), which increased over time. In addition, PDC could substantially augment the transcription and protein levels of acetyl-CoA carboxylases alpha (ACACA) and fatty acid synthase (FASN) in LMH cells (p < 0.01). (2) Compared with the PDC-exposure group, the addition of 8 µmol/L NANO-Se after 12 h of PDC treatment could significantly increase the cell viability (p < 0.01) but decreased over time; the levels of TG and LDL-C in LMH cells declined markedly (p < 0.01). In addition, the transcription and protein levels of ACACA and FASN in LMH cells were significantly reduced (p < 0.01). (3) The LMH cells were cultured in advance with 8 µmol/L NANO-Se for 12 h and then with PDC for 24 h. The obtained results were similar to the above. There were no obvious differences in TG and LDL-C levels (p > 0.05). However, significant differences were found in the activity of LMH cells and the expression of genes related to lipid metabolism (p < 0.05).All these results suggest that the exposure to PDC promotes the increase of lipid synthesis in LMH cells and causes disorders in the lipid metabolism. Moreover, NANO-Se can partially attenuate the damage caused by PDC through down-regulating of the lipid metabolism-related genes (ACACA and FASN) in LMH cells.

Down-regulation of ACACA suppresses the malignant progression of Prostate Cancer through inhibiting mitochondrial potential.

Background and aim: Silencing the expression of ACACA inhibits cell proliferation and induces apoptosis in prostate cancer LNCaP cells. However, the role of ACACA in other prostate cancer cells is not fully understood. Also, the effect of knocking down ACACA gene on mitochondria remains unclear. This study aimed to discover the specific role of ACACA gene in prostate cancer (PCa) DU145 and PC3 cells as well as its effects on mitochondrial potential. Methods: The expression of ACACA gene was detected in human prostate cancer tissue microarrays and assessed in different clinical stages. Then, prostate cancer cell lines with low expression of ACACA were constructed to evaluate the changes in their cell cycle, proliferation, and metabolites. The effect of ACACA on tumor formation in vivo was analyzed. Also, mito-ATP production, mitochondrial staining, and mtDNA, nicotinamide adenine dinucleotide (NAD+/NADH), and reactive oxygen species (ROS) levels were detected. Results: ACACA was expressed more strongly in prostate cancer tissues. The expression level of ACACA was higher in patients with advanced PCa than in patients with lower grades. The proliferation ability reduced in ACACA-knockdown cells. In in vivo tests, the tumor volume and weight were lower in the experimental group than in the control group. Mito-ATP production decreased significantly after ACACA suppression, mtDNA levels and MitoTracker staining decreased in the experimental group. The ratio of NAD+/NADH and ROS levels were upregulated in the experimental group. Conclusion: Targeting ACACA gene and mitochondria might serve as a novel therapy for prostate cancer treatment.

ssc-miR-451 Regulates Porcine Primary Adipocyte Differentiation by Targeting ACACA.

miRNA is a small non-coding RNA, which plays an important role in diverse biological processes. In the present study, we explore the effect of ssc-miR-451 on porcine adipose development and meat quality. We observed that ssc-miR-451 was downregulated during porcine primary adipocyte differentiation. Overexpression of ssc-miR-451 inhibited adipogenic differentiation, while inhibition of ssc-miR-451 promoted adipogenic differentiation. The dual luciferase reporter system indicated Acetyl-CoA carboxylase alpha (ACACA) as a target gene of ssc-miR-451. Correlation analysis negatively correlated miR-451 expression with intramuscular fat content (IMF) and positively correlated ACACA expression with IMF. Further analysis of fatty acid composition revealed that pigs with high expression of ssc-miR-451 had higher monounsaturated fatty acid (MUFA) and lower polyunsaturated fatty acid (PUFA). Taken together, our study suggests that ssc-miR-451 regulates lipid deposition and fatty acid composition by targeting ACACA, and ssc-miR-451 may serve as a potential genetic marker to improve pork quality.

Antagonistic effects of nano-selenium on broilers hepatic injury induced by Cr(VI) poisoning in AMPK pathway.

Cr (chromium, with common valence states of III and VI) is one of the common broiler feed additives. Liver injury and metabolic disorders could be caused by Cr(VI) (hexavalent chromium) poisoning in broilers. Oxidative damage and metabolic disorders of organisms caused by heavy metals could be antagonized by nano-Se (nano-selenium). Nano-Se was chosen to study the antagonism of Cr(VI) poisoning in broilers. AMPK (Adenosine 5,-monophosphate-activated protein kinase) is known as a "cell energy regulator" and plays a key regulatory role in carbohydrate and lipid metabolism. AMPK pathway and ACACA/CPT1A two genes were selected to study the prevention and treatment of nano-Se on Cr(VI) poisoning in broilers and its molecular mechanism. For this purpose, 180 1-day-old AA (Arbor Acres) broilers were selected and randomly divided into 6 groups (n = 30) for further testing. After feeding as planned for 35 days, the livers of such broilers were taken for further examination including histopathological examination, differential gene expression analysis, and further validation on both mRNA and protein levels using related techniques like RT-qPCR, western blot, and immunohistochemistry (IHC). The histopathological examination suggested that the liver cells of the Cr(VI) poisoning group were more severely injured than the nano-Se addition group. RT-qPCR results showed that the relative expression of ACACA gene in the Cr(VI) poisoning group was significantly increased (P < 0.05), while the CPT1A gene's expression was significantly decreased (P < 0.01). Those results were reversed in the nano-Se addition group. Western blot results were consistent with RT-qPCR and both suggested antagonism of nano-Se on Cr(VI). Through morphological and histopathological observation, as well as the measurement of the mRNA and protein expression levels of ACACA and CPT1A genes in AMPK pathway, it was confirmed that nano-Se has certain preventive and protective effects on Cr(VI) poisoning in broiler chickens. Furthermore, the adverse effects of Cr(VI) on carbohydrate and lipid metabolism in broilers can be antagonized by nano-Se through AMPK pathway. A new method and experimental basis were provided to the future study of Cr(VI) poisoning in broilers.

Impact of SNPs in ACACA, SCD1, and DGAT1 Genes on Fatty Acid Profile in Bovine Milk with Regard to Lactation Phases.

Milk fat is a dietary source of fatty acids (FA), which can be health promoting or can increase risks of some diseases. FA profile composition depends on many factors, among them gene polymorphism. This study analyzed the relation between polymorphism of acetyl-CoA carboxylase α (ACACA), stearoyl-CoA desaturase 1 (SCD1), diacylglycerol acyltransferase 1 (DGAT1) genes with FA profile in milk from Polish Holstein-Friesian cattle and determined changes of FA percentage during lactation with regard to polymorphism. Milk samples were collected twice: during the first phase of lactation (<90 Days in milk; DIM) and at the end of lactation (>210 DIM). During the first milk collection, blood samples were taken to analyze three chosen single nucleotide polymorphisms (SNPs): AJ312201.1g.1488C > G SNP in ACACA gene, A293V SNP in SCD1 gene, and K232A SNP in DGAT1 gene. Increased concentration of FA that are less beneficial for human health and have lower concentration of healthy FA in homozygotes: GG in ACACA, VV in SCD1, and KK in DGAT1 were observed, as well as a strong influence of the analyzed genes on FA with 18C atoms was also found. Moreover, it was demonstrated that lactation phase significantly affected FA percentage in milk depending on the phenotype. These results may contribute their part to knowledge toward obtaining more beneficial milk composition.

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2).

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. METHODS: Nrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control. Measures of whole-body glucose homeostasis, histologic assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis, and oxidative stress were performed in livers from these animals. RESULTS: TBE-31 treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31 treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, while increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31 treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis, and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in livers of HFFr-fed Nrf2-null mice. CONCLUSIONS: Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

A maternal high-fat, high-sucrose diet alters insulin sensitivity and expression of insulin signalling and lipid metabolism genes and proteins in male rat offspring: effect of folic acid supplementation.

A maternal high-fat, high-sucrose (HFS) diet alters offspring glucose and lipid homoeostasis through unknown mechanisms and may be modulated by folic acid. We investigated the effect of a maternal HFS diet on glucose homoeostasis, expression of genes and proteins associated with insulin signalling and lipid metabolism and the effect of prenatal folic acid supplementation (HFS/F) in male rat offspring. Pregnant Sprague-Dawley rats were randomly fed control (CON), HFS or HFS/F diets. Offspring were weaned on CON; at postnatal day 70, fasting plasma insulin and glucose and liver and skeletal muscle gene and protein expression were measured. Treatment effects were assessed by one-way ANOVA. Maternal HFS diet induced higher fasting glucose in offspring v. HFS/F (P=0·027) and down-regulation (P<0·05) of genes coding for v-Akt murine thymoma viral oncogene homolog 2, resistin and v-Raf-1 murine leukaemia viral oncogene homolog 1 (Raf1) in offspring skeletal muscle and acetyl-CoA carboxylase (Acaca), fatty acid synthase and phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit ß in offspring liver. Skeletal muscle neuropeptide Y and hepatic Kruppel-like factor 10 were up-regulated in HFS v. CON offspring (P<0·05). Compared with CON, Acaca and Raf1 protein expression levels were significantly lower in HFS offspring. Maternal HFS induced higher homoeostasis model of assessment index of insulin resistance v. CON (P=0·030) and HFS/F was associated with higher insulin (P=0·016) and lower glucose (P=0·025). Maternal HFS diet alters offspring insulin sensitivity and de novo hepatic lipogenesis via altered gene and protein expression, which appears to be potentiated by folate supplementation.

Dataset of the human homologues and orthologues of lipid-metabolic genes identified as DAF-16 targets their roles in lipid and energy metabolism.

The data presented in this article are related to the review article entitled 'Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis' (Saavedra-Garcia et al., 2017) [24]. Here, we have matched the DAF-16/FOXO3 downstream genes with their respective human orthologues and reviewed the roles of these targeted genes in FA metabolism. The list of genes listed in this article are precisely selected from literature reviews based on their functions in mammalian FA metabolism. The nematode Caenorhabditis elegans gene orthologues of the genes are obtained from WormBase, the online biological database of C. elegans. This dataset has not been uploaded to a public repository yet.