Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis.
Zhang X, Zhang J, Sun H, Liu X, Zheng Y, Xu D, Wang J, Jia D, Han X, Liu F, Nie J, Shi Y
Cellular and Molecular Gastroenterology and Hepatology. 2019;7(4):763-781. doi: 10.1016/j.jcmgh.2019.02.002. Epub 2019 Mar 1.
BACKGROUND & AIMS: Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases. Here, we investigated the role of LPGAT1 in regulating the onset of diet-induced obesity and its related hepatosteatosis because polymorphisms of the LPGAT1 gene promoter were strongly associated with susceptibility to obesity in Pima Indians.
METHODS: Mice with whole-body knockout of LPGAT1 were generated to investigate the role of PG remodeling in NAFLD.
RESULTS: LPGAT1 deficiency protected mice from diet-induced obesity, but led to hepatopathy, insulin resistance, and NAFLD as a consequence of oxidative stress, mitochondrial DNA depletion, and mitochondrial dysfunction.
CONCLUSIONS: This study identified an unexpected role of PG remodeling in obesity, linking mitochondrial dysfunction to NAFLD.
Age-related changes in the marmoset gut microbiome
Reveles KR, Patel S, Forney L, Ross CN
American Journal of Primatology. 2019 Feb;81(2):e22960. doi: 10.1002/ajp.22960. Epub 2019 Feb 25.
The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non-human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2-5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur’s Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome-targeted therapies to improve healthspan and lifespan.
Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis.
Puchalska P, Martin SE, Huang X, Lengfeld JE, Daniel B, Graham MJ, Han X, Nagy L, Patti GJ, Crawford PA
Cell Metabolism. 2019 Feb 5;29(2):383-398.e7. doi: 10.1016/j.cmet.2018.10.015. Epub 2018 Nov 15.
Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.
Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: Relationship to neuroimaging and CSF biomarkers.
Nho K, Kueider-Paisley A, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X, Kastenmüller G, Jia W, Xie G, Ahmad S, Hankemeier T, van Duijn CM, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, Saykin AJ, Kaddurah-Daouk R; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.
Alzheimer’s & Dementia. 2019 Feb;15(2):232-244. doi: 10.1016/j.jalz.2018.08.012. Epub 2018 Oct 15.
INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer’s disease (AD) including neuroinflammation and amyloid-β deposition.
METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET).
RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 (“A”) and three with CSF p-tau181 (“T”) (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (“N”), respectively (corrected P < .05).
DISCUSSION: This is the first study to show serum-based BA metabolites are associated with “A/T/N” AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
Rapamycin and Alzheimer’s disease: Time for a clinical trial?
Kaeberlein M, Galvan V
Science Translational Medicine. 2019 Jan 23;11(476). pii: eaar4289. doi: 10.1126/scitranslmed.aar4289.
The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer’s disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer’s disease. We argue that such clinical trials should be undertaken.
Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans.
Aiping Xu, Zhao Zhang, Su‐Hyuk Ko, Alfred L. Fisher, Zhijie Liu, Lizhen Chen
Aging Cell. 14 January 2019. doi: 10.1111/acel.12884. [Epub ahead of print].
Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.
Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors.
Gao CZ, Dong W, Cui ZW, Yuan Q, Hu XM, Wu QM, Han X, Xu Y, Min ZL
Journal of Enzyme Inhibition and Medicinal Chemistry. 2019 Dec;34(1):150-162. doi: 10.1080/14756366.2018.1530224.
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-An emerging role for gut microbiome.
MahmoudianDehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G, Louie G, Kueider-Paisley A, Moseley MA, Thompson JW, St John Williams L, Tenenbaum JD, Blach C, Baillie R, Han X, Bhattacharyya S, Toledo JB, Schafferer S, Klein S, Koal T, Risacher SL, Kling MA, Motsinger-Reif A, Rotroff DM, Jack J, Hankemeier T, Bennett DA, De Jager PL, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, van Duijn CM, Saykin AJ, Kastenmüller G, Kaddurah-Daouk R; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.
Alzheimer’s & Dementia. 2019 Jan;15(1):76-92. doi: 10.1016/j.jalz.2018.07.217. Epub 2018 Oct 15.
INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer’s disease (AD).
METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.
RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.
DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
Effects of intravenous AICAR (5-aminoimidazole-4-carboximide riboside) administration on insulin signaling and resistance in premature baboons, Papio sp.
Blanco CL, Gastaldelli A, Anzueto DG, Winter LA, Seidner SR, McCurnin DC, Liang H, Javors MA, DeFronzo RA, Musi N
PLoS one. 2018 Dec 12;13(12):e0208757. doi: 10.1371/journal.pone.0208757. eCollection 2018.
Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5′ AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects.
Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure.
Wang C, Liu F, Frisch-Daiello JL, Martin S, Patterson TA, Gu Q, Liu S, Paule MG, Hanig JP, Slikker W Jr, Crawford PA, Wang C, Han X
Analytica Chimica Acta. 2018 Dec 11;1037:87-96. doi: 10.1016/j.aca.2017.11.052. Epub 2017 Nov 30.
Although numerous studies have raised public concerns regarding the safety of anesthetics including sevoflurane in children, the biochemical mechanisms leading to anesthetics-induced neurotoxicity remain elusive. Moreover, potential biomarker(s) for early detection of general anesthetics-induced brain injury are urgent for public health. We employed an enabling technology of shotgun lipidomics and analyzed nearly 20 classes and subclasses of lipids present in the blood serum of postnatal day (PND) 5 or 6 rhesus monkeys temporally collected after exposure to sevoflurane at a clinically relevant concentration or room-air as control. Lipidomics analysis revealed numerous significant anesthetic-induced changes of serum lipids and their metabolites as well as short chain acylcarnitines in the brain and cerebrospinal fluid after anesthetic exposure. These include decreased carnitine and acylcarnitines, unchanged triacylglycerol mass but accumulation of 16:0 and 18:1 fatty acyl chains in the triacylglycerol pool, losses of polyunsaturated fatty acids in both non-esterified fatty acid and phospholipid pools, and increased 4-hydroxynonenal content as early as 2 h after sevoflurane exposure. Importantly, the amounts of short chain acylcarnitines in the brain and cerebrospinal fluid were also significantly reduced after anesthetic exposure. We propose that this serum lipidomic profile can serve as indicative of neuronal damage. Our results reveal that sevoflurane exposure induces an energy deficient state in the brain evidenced by reduced free and acyl carnitine contents, as well as the presence of a pro-inflammatory state in the exposed animals, providing deep insights into the underlying mechanisms responsible for anesthetic-induced neurotoxicity.