Metabolism
Abstract
The angiopoietin-like protein ANGPTL8 (A8) is one of three ANGPTLs (A8, A3, A4) that coordinate changes in triglyceride (TG) delivery to tissues by inhibiting lipoprotein lipase (LPL), an enzyme that hydrolyzes TG. Previously we showed that A8, which is expressed in liver and adipose tissue, is required to redirect dietary TG from oxidative to storage tissues following food intake. Here we show that A8 from liver and adipose tissue have different roles in this process. Mice lacking hepatic A8 have no circulating A8, high intravascular LPL activity, low plasma TG levels, and evidence of decreased delivery of dietary lipids to adipose tissue. In contrast, mice lacking A8 in adipose tissue have higher postprandial TG levels and no alteration in fatty acid composition in adipocytes. Expression of A8, together with A4, in cultured cells reduced A4 secretion and A4-mediated LPL inhibition. Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4. These combined actions of A8 ensure that TG stores are rapidly replenished and sufficient energy is available until the next meal.
Authors
Federico Oldoni, Haili Cheng, Serena Banfi, Viktoria Gusarova, Jonathan C. Cohen, Helen H. Hobbs
Abstract
Orphan nuclear receptor estrogen-related receptor (ERR)γ stimulates bile acid production, however, the role and the regulatory mechanism of ERRγ in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERRγ and suggests a novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERRγ. We observed that hepatic expression of Sirt6 is repressed while that of ERRγ is upregulated in murine cholestasis models. Hepatocyte-specific Sirt6 knockout mice were more severely injured following a bile duct ligation (BDL) compared to wild-type mice and adenoviral re-expression of Sirt6 reversed liver damage and fibrosis as demonstrated by biochemical and histological analyses. Mechanistically, Sirt6 deacetylated ERRγ, thereby destabilized ERRγ and inhibited its transcriptional activity. Elimination of hepatic ERRγ using Ad-shERRγ abolished the deleterious effects of Sirt6 deficiency, while ERRγ overexpression aggravated cholestatic liver injury. Administration of a Sirt6 deacetylase activator prevented BDL-induced liver damage and fibrosis. In patients with cholestasis, Sirt6 expression was decreased while total- and acetylated-ERRγ levels were increased, confirming negative regulation of ERRγ by Sirt6. Thus, Sirt6 activation represents a new therapeutic strategy for treating cholestatic liver injury.
Authors
Lihua Hao, In Hyuk Bang, Jie Wang, Yuancheng Mao, Jae Do Yang, Soon-Young Na, Jeong Kon Seo, Hueng-Sik Choi, Eun Ju Bae, Byung-Hyun Park
Abstract
BACKGROUND. Metabolically healthy obesity (MHO) and metabolically healthy overweight (MH-OW) have been suggested to be an important and emerging phenotype with an increased risk of cardiovascular disease (CVD). However, whether MHO and MH-OW are associated with all-cause mortality remains inconsistent. METHODS. The association of MHO and MH-OW and all-cause mortality was determined in China community-based prospective cohort study (Kailuan Study) including 93,272 adults at baseline. Data were analyzed from 2006 to 2017. Participants were categorized into six mutually exclusive groups according to the body mass index (BMI) and metabolic syndrome (MetS) status. The primary outcome is all-cause death, whereas accidental deaths were excluded. RESULTS. During a median follow-up of 11.04 years (interquartile range: 10.74-11.22 years), 8,977 deaths occurred. Compared to healthy participants with normal BMI (MH-NW), MH-OW had lowest risk of all-cause mortality (multivariate-adjusted hazard ratio [aHR]: 0.926; 95% confidence interval [CI]: 0.861 to 0.997), whereas there was no increased or decreased risk for MHO (aHR: 1.009; 95% CI: 0.886 to 1.148). Stratified analyses and sensitivity analyses further validated that nonsignificant association between MHO and all-cause mortality. CONCLUSIONS. Overweight and obesity do not predicate increased risk of all-cause mortality in metabolic healthy Chinese individuals.
Authors
Qiuyue Tian, Anxin Wang, Yingting Zuo, Shuohua Chen, Haifeng Hou, Wei Wang, Shouling Wu, Youxin Wang
Abstract
Kidney disease is one of the most devastating complications of diabetes, and tubular atrophy predicts diabetic kidney disease (DKD) progression to end stage renal disease. We have proposed that fatty acids bound to albumin contribute to tubular atrophy by inducing lipotoxicity, following filtration across damaged glomeruli, and subsequent proximal tubule reabsorption by a fatty acid transport protein-2 (FATP2)-dependent mechanism. To address this possibility, genetic (Leprdb/db eNOS-/-) and induced (high fat diet plus low dose streptozotocin) mouse models of obesity and DKD, were bred with global FATP2 gene (Slc27a2)-deleted mice, and then phenotyped. DKD-prone mice with the Slc27a2-/- genotype demonstrated normalization of glomerular filtration rate, reduced albuminuria, improved kidney histopathology, and longer lifespan compared to diabetic Slc27a2+/+ mice. Genetic and induced DKD-prone Slc27a2-/- mice also exhibited markedly reduced fasting plasma glucose, with mean values approaching euglycemia, despite increased obesity and decreased physical activity. Glucose lowering in DKD-prone Slc27a2-/- mice was accompanied by beta-cell hyperplasia and sustained insulin secretion. Together, our data indicate that FATP2 uniquely regulates DKD pathogenesis by a combined lipotoxicity and glucotoxicity (glucolipotoxicity) mechanism.
Authors
Shenaz Khan, Robert J. Gaivin, Caroline Abramovich, Michael Boylan, Jorge Calles, Jeffrey R. Schelling
Abstract
De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating and hepatic-TG. The percentage of TG-rich lipoprotein particle (TRLP)-TG derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated with levels similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG x % DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered HbA1c and hepatic-TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic-TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD.These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions, and improvements in hepatic steatosis and dyslipidemia.
Authors
Annah P. Baykal, Elizabeth J. Parks, Robert Shamburek, Majid M. Syed-Abdul, Shaji K. Chacko, Elaine Cochran, Megan Startzell, Ahmed M. Gharib, Ronald Ouwerkerk, Khaled Z. Abd-Elmoniem, Peter J. Walter, Mary Walter, Ranganath Muniyappa, Stephanie T. Chung, Rebecca J. Brown
Abstract
It has been proposed that unmethylated insulin promoter fragments in plasma derive exclusively from β-cells, reflect their recent demise and can be used to assess β-cell damage in type 1 diabetes. Herein we describe an ultrasensitive assay for detection of a β-cell-specific DNA methylation signature, by simultaneous assessment of six DNA methylation markers, that identifies β-cell DNA in mixtures containing as little as 0.03% β-cell DNA (less than one β-cell genome equivalent). With this assay, plasma from non-diabetic individuals (N=218, aged 4-78 years) contained on average only one β-cell genome equivalent/ml. As expected, β-cell cfDNA was significantly elevated in islet transplant recipients shortly after transplantation. We also detected β-cell cfDNA in a patient with KATP congenital hyperinsulinism where substantial β-cell turnover is thought to occur. Strikingly, in contrast to previous reports, we observed no elevation of β-cell-derived cfDNA in autoantibody positive subjects at-risk for type 1 diabetes (N=32), individuals with recent-onset type 1 diabetes (<4 months, N=92), or those with a long-standing disease (>4 months, N=38). We discuss the utility of sensitive beta-cell cfDNA analysis and potential explanations for the lack of a β-cell cfDNA signal in T1D.
Authors
Daniel Neiman, David Gillis, Sheina Piyanzin, Daniel Cohen, Ori Fridlich, Joshua Moss, Aviad Zick, Tal Oron, Frida Sundberg, Gun Forsander, Oskar Skog, Olle Korsgren, Floris Levy-Khademi, Dan Arbell, Saar Hashavya, A.M. James Shapiro, Cate Speake, Carla Greenbaum, Jennifer Hosford, Amanda Posgai, Mark A. Atkinson, Benjamin Glaser, Desmond Schatz, Ruth Shemer, Yuval Dor
Abstract
Reprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks. To investigate metabolic effects of SARS-COV-2 infection, we evaluated serum metabolites of COVID-19 patients (n = 33; diagnosed by nucleic acid testing), as compared to COVID-19-negative controls (n = 16). Targeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.
Authors
Tiffany Thomas, Davide Stefanoni, Julie A. Reisz, Travis Nemkov, Lorenzo Bertolone, Richard O. Francis, Krystalyn E. Hudson, James C. Zimring, Kirk C. Hansen, Eldad A. Hod, Steven L. Spitalnik, Angelo D’Alessandro
Abstract
BACKGROUND While saturated fat intake leads to insulin resistance and nonalcoholic fatty liver, Mediterranean-like diets enriched in monounsaturated fatty acids (MUFA) may have beneficial effects. This study examined effects of MUFA on tissue-specific insulin sensitivity and energy metabolism.METHODS A randomized placebo-controlled cross-over study enrolled 16 glucose-tolerant volunteers to receive either oil (OIL, ~1.18 g/kg), rich in MUFA, or vehicle (VCL, water) on 2 occasions. Insulin sensitivity was assessed during preclamp and hyperinsulinemic-euglycemic clamp conditions. Ingestion of 2H2O/acetaminophen was combined with [6,6-2H2]glucose infusion and in vivo 13C/31P/1H/ex vivo 2H-magnet resonance spectroscopy to quantify hepatic glucose and energy fluxes.RESULTS OIL increased plasma triglycerides and oleic acid concentrations by 44% and 66% compared with VCL. Upon OIL intervention, preclamp hepatic and whole-body insulin sensitivity markedly decreased by 28% and 27%, respectively, along with 61% higher rates of hepatic gluconeogenesis and 32% lower rates of net glycogenolysis, while hepatic triglyceride and ATP concentrations did not differ from VCL. During insulin stimulation hepatic and whole-body insulin sensitivity were reduced by 21% and 25%, respectively, after OIL ingestion compared with that in controls.CONCLUSION A single MUFA-load suffices to induce insulin resistance but affects neither hepatic triglycerides nor energy-rich phosphates. These data indicate that amount of ingested fat, rather than its composition, primarily determines the development of acute insulin resistance.TRIAL REGISTRATION ClinicalTrials.gov NCT01736202.FUNDING German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Portugal Foundation for Science and Technology, European Regional Development Fund, and Rede Nacional de Ressonancia Magnética Nuclear.
Authors
Theresia Sarabhai, Sabine Kahl, Julia Szendroedi, Daniel F. Markgraf, Oana-Patricia Zaharia, Cristina Barosa, Christian Herder, Frithjof Wickrath, Pavel Bobrov, Jong-Hee Hwang, John Griffith Jones, Michael Roden
Abstract
EIF2AK4, which encodes the amino acid deficiency–sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.
Authors
Ayumi Kanno, Shun-ichiro Asahara, Ayuko Furubayashi, Katsuhisa Masuda, Risa Yoshitomi, Emi Suzuki, Tomoko Takai, Maki Kimura-Koyanagi, Tomokazu Matsuda, Alberto Bartolome, Yushi Hirota, Norihide Yokoi, Yuka Inaba, Hiroshi Inoue, Michihiro Matsumoto, Kenichi Inoue, Takaya Abe, Fan-Yan Wei, Kazuhito Tomizawa, Wataru Ogawa, Susumu Seino, Masato Kasuga, Yoshiaki Kido
Abstract
There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease, but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibit increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.
Authors
Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C. M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler
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