Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). We aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-ketoacids (BCKAs) and hepatic BCKDK expression are associated with the presence and severity of non-alcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKA, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 bariatric surgery patients with severe obesity (BMI > 35 kg/m2) with scored liver biopsy samples. Metabolite principal component analysis (PCA) factors, BCKA, branched-chain amino acids (BCAA), and the BCKA:BCAA ratio were tested for associations with steatosis grade and presence of non-alcoholic steatohepatitis (NASH). Of all analytes tested, only the valine-derived BCKA, α-ketoisovalerate, and the BCKA:BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from two independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowers BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.
Thomas Grenier-Larouche, Lydia Coulter Kwee, Yann Deleye, Paola Leon-Mimila, Jacquelyn M. Walejko, Robert W. McGarrah, Simon Marceau, Sylvain Trahan, Christine Racine, André C. Carpentier, Aldons J. Lusis, Olga Ilkayeva, Marie-Claude Vohl, Adriana Huertas-Vazquez, Andre Tchernof, Svati H. Shah, Christopher B. Newgard, Phillip J. White
Developmental cardiac tissue is regenerative while operating under low oxygen. After birth, ambient oxygen is associated with cardiomyocyte cell cycle exit and regeneration. Likewise, cardiac metabolism undergoes a shift with cardiac maturation. Whether there are common regulators of cardiomyocyte cell cycle linking metabolism to oxygen tension remains unknown. The objective of the study is to determine whether mitochondrial UCP2 is a metabolic oxygen sensor regulating cardiomyocyte cell cycle. Neonatal rat ventricular myocytes (NRVMs) under moderate hypoxia showed increased cell cycle activity and UCP2 expression. NRVMs exhibited a metabolic shift towards glycolysis, reduced citrate synthase, mtDNA, ΔΨm and DNA damage/oxidative stress while loss of UCP2 reversed this phenotype. Next, WT and UCP2KO mice kept under hypoxia for 4 weeks showed significant decline in cardiac function that was more pronounced in UCP2KO animals. Cardiomyocyte cell cycle activity was reduced while fibrosis and DNA damage was significantly increased in UCP2KO animals compared to WT under hypoxia. Mechanistically, UCP2 increased acetyl-CoA levels, histone acetylation and altered chromatin modifiers linking metabolism to cardiomyocyte cell cycle under hypoxia. Here, we show a novel role for mitochondrial UCP2 as an oxygen sensor regulating cardiomyocyte cell cycle activity, acetyl-CoA levels and histone acetylation in response to moderate hypoxia.
Vagner O.C. Rigaud, Clare Zarka, Justin Kurian, Daria Harlamova, Andrea Elia, Nicole Kasatkin, Jaslyn Johnson, Michael Behanan, Lindsay Kraus, Hannah Pepper, Nathaniel W. Snyder, Sadia Mohsin, Steven Houser, Mohsin Khan
The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent the decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
Aina Lluch, Sonia R. Veiga, Jèssica Latorre, José M. Moreno-Navarrete, Núria Bonifaci, Van Dien Nguyen, You Zhou, Marcus Horing, Gerhard Liebisch, Vesa M. Olkkonen, David Llobet-Navas, George Thomas, Ruth Rodriguez-Barrueco, José M. Fernández-Real, Sara C. Kozma, Francisco J. Ortega
Infantile spasms syndrome (IS) is a devastating early-onset epileptic encephalopathy associated with poor neurodevelopmental outcomes. When first-line treatment options, including adrenocorticotropic hormone and vigabatrin, are ineffective, the ketogenic diet (KD) is often employed to control seizures. Since the therapeutic impact of the KD is influenced by the gut microbiota, we examined whether targeted microbiota manipulation, mimicking changes induced by the KD, would be valuable in mitigating seizures. Employing a rodent model of symptomatic IS, we show that both the KD and antibiotic administration reduce spasm frequency and are associated with improved developmental outcomes. Spasm reductions were accompanied by specific gut microbial alterations, including increases in Streptococcus thermophilus and Lactococcus lactis. Mimicking the fecal microbial alterations in a targeted probiotic, we administered these species in a 5:1 ratio. Targeted probiotic administration reduced seizures and improved locomotor activities in control diet–fed animals, similar to KD-fed animals, while a negative control (Ligilactobacillus salivarius) had no impact. Probiotic administration also increased antioxidant status and decreased proinflammatory cytokines. Results suggest that a targeted probiotic reduces seizure frequency, improves locomotor activity in a rodent model of IS, and provides insights into microbiota manipulation as a potential therapeutic avenue for pediatric epileptic encephalopathies.
Chunlong Mu, Naghmeh Nikpoor, Thomas A. Tompkins, Anamika Choudhary, Melinda Wang, Wendie N. Marks, Jong M. Rho, Morris H. Scantlebury, Jane Shearer
Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). ApoC-III also induces sterile inflammation via inflammasome activation, another CVD risk factor. It remains unclear if therapeutic apoC-III lowering reduces CVD risk, nor is it understood if the CVD correlation depends on the lipid-lowering or anti-inflammatory properties. Therefore, we determined the impact of interventional apoC-III lowering on atherogenesis via apoC-III antisense oligonucleotide (ASO) administration in two hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides (Apoe-/-Ndst1f/fAlb-Cre+, Ldlr-/-Ndst1f/fAlb-Cre+) and in a third lipid-refractory model where the ASO cannot lower plasma triglycerides (Ldlr-/-Lrp1f/fAlb-Cre+). A high-cholesterol Western diet ApoC-III ASO treatment did not alter atherosclerotic lesion size but did significantly attenuate advanced and unstable plaque development in the two triglyceride responsive mouse models. In contrast, no lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory Ldlr-/-Lrp1f/fAlb-Cre+ mice. To circumvent confounding effects of continuous high cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12-weeks of Western diet. In this diet-switch regimen, ApoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in Ldlr-/-Ndst1f/fAlb-Cre+ mice. Again, ApoC-III ASO treatment did not alter triglyceride levels, lesion development and lesion composition in Ldlr-/-Lrp1f/fAlb-Cre+ mice after the diet-switch. Thus, therapeutic apoC-III targeting increased fibrous cap thickness, and reduced necrotic core area and lesion size after diet intervention when triglyceride-lowering is achieved in murine models. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability.
Bastian Ramms, Sohan Patel, Xiaoli Sun, Ariane R. Pessentheiner, G. Michelle Ducasa, Adam E. Mullick, Richard G. Lee, Rosanne M. Crooke, Sotirios Tsimikas, Joseph L. Witztum, Philip L.S.M. Gordts
Insulin secretion from pancreatic β cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that β cell–specific deletion of Zfp148 (β-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from β‑Zfp148KO and control mice fed both a chow and a Western-style diet. β-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. β-Zfp148KO islets also exhibited elevated sensitivity to amino acid–induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of β-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, β-Zfp148KO islets displayed enhanced insulin secretion in response to l-glutamine and activation of glutamate dehydrogenase. Understanding pathways controlled by ZFP148 may provide promising strategies for improving β cell function that are robust to the metabolic challenge imposed by a Western diet.
Christopher H. Emfinger, Eleonora de Klerk, Kathryn L. Schueler, Mary E. Rabaglia, Donnie S. Stapleton, Shane P. Simonett, Kelly A. Mitok, Ziyue Wang, Xinyue Liu, Joao A. Paulo, Qinq Yu, Rebecca L. Cardone, Hannah R. Foster, Sophie L. Lewandowski, José C. Perales, Christina M. Kendziorski, Steven P. Gygi, Richard G. Kibbey, Mark P. Keller, Matthias Hebrok, Matthew J. Merrins, Alan D. Attie
Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium, however the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor, farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express eGFP in ISC/progenitor cells and performed RNA-seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and a FXR antagonist. RNA-seq of ISCs revealed that bile acids receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and two different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate towards EEC differentiation through bile acid signaling.
Ki-Suk Kim, Bailey C.E. Peck, Yu-Han Hung, Kieran Koch-Laskowski, Landon Wood, Priya H. Dedhia, Jason R. Spence, Randy J. Seeley, Praveen Sethupathy, Darleen A. Sandoval
HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR–double KO (ALKO), and ALDH2 rs671–knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency–induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
Luxiao Li, Shanshan Zhong, Rui Li, Ningning Liang, Lili Zhang, Shen Xia, Xiaodong Xu, Xin Chen, Shiting Chen, Yongzhen Tao, Huiyong Yin
Mothers that underwent bariatric surgery are at higher risk for delivering a small-for-gestational age (SGA) infant. This phenomenon is attributed to malabsorption and rapid weight loss following surgery. We compared pregnancy outcomes in lean mice that underwent sham surgery or sleeve gastrectomy (SG). SG led to a reduction in glucose levels and an increase in postprandial levels of glucagon-like peptide 1 (Glp1) without affecting mice weight during pregnancy. Pups of SG-operated mice (SG pups) were born SGA. The placenta and pancreas of the pups were not affected by SG, although a high-fat diet caused hepatic steatosis and glucose intolerance in male SG pups. Treatment with a Glp1 receptor antagonist during pregnancy normalized the birth weight of SG pups and diminished the adverse response to a high-fat diet without affecting glucose levels of pregnant mice. The antagonist did not affect the birth weight of pups of sham-operated mice. Our findings link elevated Glp1 signaling, rather than weight loss, to the increased prevalence of SGA births following bariatric surgery with metabolic consequences for the offspring. The long-term effects of bariatric surgery on the metabolic health of offspring of patients require further investigation.
Liron Hefetz, Rachel Ben-Haroush Schyr, Michael Bergel, Yhara Arad, Doron Kleiman, Hadar Israeli, Itia Samuel, Shira Azulai, Arnon Haran, Yovel Levy, Dana Sender, Amihai Rottenstreich, Danny Ben-Zvi
BACKGROUND. Although traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed. METHODS. In a prospective, observational study, 795 subjects had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E (ApoE)-containing HDL-cholesterol. Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiographic (CCTA) characterization (Medis, Qangio) of total (TB), non-calcified (NCB) and fibrous plaque burden (FB) was performed in a sub-cohort (n=300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured. RESULTS. Most patients had a clinical diagnosis of coronary artery disease (CAD) (n=80.4% of 795), with mean age of 59 years, male (57%) and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P<0.001), with higher CAC as compared to high ApoE-HDL-C. On quantitative CCTA, high ApoE-HDL-C group had lower NCB (β=-0.24, P=0.0001), which tended to be significant in fully adjusted model (β=-0.32, P=0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β=0.31; P=0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P=0.0001) in a fully adjusted model. CONCLUSIONS. ApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity. CLINICAL TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Nidhi Patel, Khaled M. Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin Playford, Amit K. Dey, Aarthi Reddy, Heather L. Teague, Michael Stagliano, Marcelo Amar, Marcus Y. Chen, Nehal Mehta, Alan T. Remaley
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