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Adiponectin Alleviates Diet-Induced Inflammation in the Liver by Suppressing MCP-1 Expression and Macrophage Infiltration

Jiyoon Ryu, Jason T Hadley, Zhi Li, Feng Dong, Huan Xu, Xiaoban Xin, Ye Zhang, Cang Chen, Senlin Li, Xiaoning Guo, Jared L Zhao, Robin J Leach, Muhammad A Abdul-Ghani, Ralph A DeFronzo, Amrita Kamat, Feng Liu, Lily Q Dong
Diabetes. 2021 Jun;70(6):1303-1316. doi: 10.2337/db20-1073. Epub 2021 Mar 18.

Abstract:

Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte-specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-α-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.


Pontin Functions as A Transcriptional Co-activator for Retinoic Acid-induced HOX Gene Expression

Dan Tang, Zhao Zhang, Emily Zboril, Michael D Wetzel, Xinping Xu, Wei Zhang, Lizhen Chen, Zhijie Liu
J Mol Biol. 2021 Jul 9;433(14):166928. doi: 10.1016/j.jmb.2021.166928. Epub 2021 Mar 11.

Abstract:

Pontin is a AAA+ ATPase protein that has functions in various biological contexts including gene transcription regulation, chromatin remodeling, DNA damage sensing and repair, as well as assembly of protein and ribonucleoprotein complexes. Pontin is known to regulate the transcription of several important signaling pathways, including Wnt signaling. However, its role in early embryonic signaling regulation remains unclear. Retinoic acid (RA) signaling plays a central role in vertebrate development. Using an in vivo biotin tagging technology, we mapped the genome-wide binding pattern of Pontin before and after RA-induced differentiation in the pluripotent embryo carcinoma cell line NTERA-2. Biotin ChIP-seq revealed significant changes in genome-wide Pontin binding sites upon RA stimulation. We also identified a substantial amount of overlapping binding peaks between Pontin and RARα, especially on all of the HOX gene loci (A-D clusters). Pontin knockdown experiments showed that its chromatin binding at the HOX gene clusters is required for RA-induced HOX gene expression. Furthermore, we performed Global Run-On sequencing (GRO-seq) to map de novo transcripts genome-wide and found that Pontin knockdown significantly diminished nascent HOX gene transcripts, indicating that Pontin regulates HOX gene expression at the transcriptional level. Finally, proteomic analysis demonstrated that Pontin associates with chromatin organization/remodeling complexes and various other functional complexes. Altogether, we have demonstrated that Pontin is a critical transcriptional co-activator for RA-induced HOX gene activation.

Keywords: HOX gene; embryonic development; pontin; retinoic acid; transcriptional co-activator.


From DNA damage to mutations: All roads lead to aging

Jan Vijg
Ageing Res Rev. 2021 Jul:68:101316. doi: 10.1016/j.arr.2021.101316. Epub 2021 Mar 9.

Abstract:

Damage to the repository of genetic information in cells has plagued life since its very beginning 3-4 billion years ago. Initially, in the absence of an ozone layer, especially damage from solar UV radiation must have been frequent, with other sources, most notably endogenous sources related to cell metabolism, gaining in importance over time. To cope with this high frequency of damage to the increasingly long DNA molecules that came to encode the growing complexity of cellular functions in cells, DNA repair evolved as one of the earliest genetic traits. Then as now, errors during the repair of DNA damage generated mutations, which provide the substrate for evolution by natural selection. With the emergence of multicellular organisms also the soma became a target of DNA damage and mutations. In somatic cells selection against the adverse effects of DNA damage is greatly diminished, especially in postmitotic cells after the age of first reproduction. Based on an abundance of evidence, DNA damage is now considered as the single most important driver of the degenerative processes that collectively cause aging. Here I will first briefly review the evidence for DNA damage as a cause of aging since the beginning of life. Then, after discussing the possible direct adverse effects of DNA damage and its cellular responses, I will provide an overview of the considerable progress that has recently been made in analyzing a major consequence of DNA damage in humans and other complex organisms: somatic mutations and the resulting genome mosaicism. Recent advances in studying somatic mutagenesis and genome mosaicism in different human and animal tissues will be discussed with a focus on the possible mechanisms through which loss of DNA sequence integrity could cause age-related functional decline and disease.

Keywords: Aging; DNA damage; Pathogenic consequences; Somatic mutation; Transcriptional noise.


Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

Niannian Ji, Neelam Mukherjee, Ryan M Reyes, Jonathan Gelfond, Martin Javors, Joshua J Meeks, David J McConkey, Zhen-Ju Shu, Chethan Ramamurthy, Ryan Dennett, Tyler J Curiel, Robert S Svatek
J Immunother Cancer. 2021 Mar;9(3):e001941. doi: 10.1136/jitc-2020-001941.

Abstract:

Background: Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.

Methods: A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.

Results: Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).

Conclusions: Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

Keywords: immunity; immunotherapy; innate; urinary bladder neoplasms.


Lipidomics Revealed Aberrant Metabolism of Lipids Including FAHFAs in Renal Tissue in the Progression of Lupus Nephritis in a Murine Model

Changfeng Hu, Yu Du, Xiaofen Xu, Haichang Li, Qiao Duan, Zhijun Xie, Chengping Wen, Xianlin Han
Metabolites. 2021 Feb 27;11(3):142. doi: 10.3390/metabo11030142.

Abstract:

Lupus nephritis (LN) is an inflammatory renal disease of patients with systemic lupus erythematosus with lots of immune complexes deposited in kidneys. Accumulated studies have demonstrated the close relationships among dyslipidaemia, inflammation, and autoimmune response, and oxidative stress in the patients. Lipids play numerous important roles in biological process and cellular functions. Herein, shotgun lipidomics was employed to quantitatively analyze cellular lipidomes in the renal tissue of MRL/lpr mice in the progression of LN (including pre-LN and LN state) with/without treated with glucocorticoids (GCs). The levels of cytokines (i.e., TNF-α (Tumor necrosis factor alpha) and IL-6 (Interleukin 6)) in the serum were measured by ELISA (enzyme-linked immunosorbent assay) kits. Renal histopathological changes and C3 deposition in the glomeruli of the mice were also determined. Lipidomics analysis revealed that the ectopic fat deposition and the aberrant metabolism of lipids that were relevant to oxidative stress (e.g., 4-hydroxyalkenal, ceramide, lysophospholipid species, etc.) always existed in the development of LN. Moreover, the anti-inflammatory FAHFA (fatty acid ester of hydroxyl fatty acid) species in the kidney tissue could largely reflect the severity of LN. Thus, they were a potential early biomarker for LN. In addition, the study also revealed that treatment with GCs could prevent the progression of LN, but greatly aggravate the aberrant metabolism of the lipids, particularly when used for a long time.

Keywords: FAHFAs; autoimmune reaction; lipidomics; lupus nephritis; oxidative stress.


Left ventricular diastolic dysfunction and exercise intolerance in obese heart failure with preserved ejection fraction

T Jake Samuel, Dalane W Kitzman, Mark J Haykowsky, Bharathi Upadhya, Peter Brubaker, M Benjamin Nelson, W Gregory Hundley, Michael D Nelson
Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1535-H1542. doi: 10.1152/ajpheart.00610.2020. Epub 2021 Feb 12.

Abstract:

This study tested the hypothesis that early left ventricular (LV) relaxation is impaired in older obese patients with heart failure with preserved ejection fraction (HFpEF), and related to decreased peak exercise oxygen uptake (peak V̇o2). LV strain and strain rate were measured by feature tracking of magnetic resonance cine images in 79 older obese patients with HFpEF (mean age: 66 yr; mean body mass index: 38 kg/m2) and 54 healthy control participants. LV diastolic strain rates were indexed to cardiac preload as estimated by echocardiography derived diastolic filling pressures (E/e’), and correlated to peak V̇o2. LV circumferential early diastolic strain rate was impaired in HFpEF compared with controls (0.93 ± 0.05/s vs. 1.20 ± 0.07/s, P = 0.014); however, we observed no group differences in early LV radial or longitudinal diastolic strain rates. Isolating myocardial relaxation by indexing all three early LV diastolic strain rates (i.e. circumferential, radial, and longitudinal) to E/e’ amplified the group difference in early LV diastolic circumferential strain rate (0.08 ± 0.03 vs. 0.13 ± 0.05, P < 0.0001), and unmasked differences in early radial and longitudinal diastolic strain rate. Moreover, when indexing to E/e’, early LV diastolic strain rates from all three principal strains, were modestly related with peak V̇o2 (R = 0.36, -0.27, and 0.35, respectively, all P < 0.01); this response, however, was almost entirely driven by E/e’ itself, (R = -0.52, P < 0.001). Taken together, we found that although LV relaxation is impaired in older obese patients with HFpEF, and modestly correlates with their severely reduced peak exercise V̇o2, LV filling pressures appear to play a much more important role in determining exercise intolerance.NEW & NOTEWORTHY Using a multimodal imaging approach to uncouple tissue deformation from atrial pressure, we found that left ventricular (LV) relaxation is impaired in older obese patients with HFpEF, but only modestly correlates with their severely reduced peak V̇o2. In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.

Keywords: diastolic dysfunction; exercise intolerance; heart failure; heart failure with preserved ejection fraction; obesity.


High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance

Anil Kumar, Kumaran Sundaram, Jingyao Mu, Gerald W Dryden, Mukesh K Sriwastva, Chao Lei, Lifeng Zhang, Xiaolan Qiu, Fangyi Xu, Jun Yan, Xiang Zhang, Juw Won Park, Michael L Merchant, Henry C L Bohler, Baomei Wang, Shuangqin Zhang, Chao Qin, Ziying Xu, Xianlin Han, Craig J McClain, Yun Teng, Huang-Ge Zhang
Nat Commun. 2021 Jan 11;12(1):213. doi: 10.1038/s41467-020-20500-w.

Abstract:

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

Nighat Noureen, Shaofang Wu, Yingli Lv, Juechen Yang, W K Alfred Yung, Jonathan Gelfond, Xiaojing Wang, Dimpy Koul, Andrew Ludlow, Siyuan Zheng
Nat Commun. 2021 Jan 8;12(1):139. doi: 10.1038/s41467-020-20474-9.

Abstract:

Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small population of proliferating cancer cells that exhibits both high telomerase activity and cancer stemness. This study establishes a computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness.


Sex-dependent lifespan extension of Apc Min/+ FAP mice by chronic mTOR inhibition

Manish Parihar, Sherry G Dodds, Marty Javors, Randy Strong, Paul Hasty, Zelton Dave Sharp
Aging Pathobiol Ther. 2020;2(4):187-194. doi: 10.31491/apt.2020.12.039. Epub 2020 Dec 31.

Abstract:

Background: Apc Min/+ mice model familial adenomatous polyposis (FAP), a disease that causes numerous colon polyps leading to colorectal cancer. We previously showed that chronic treatment of Apc Min/+ females with the anti-aging drug, rapamycin, restored a normal lifespan through reduced polyposis and anemia prevention. Lifespan extension by chronic rapamycin in wildtype UM-HET3 mice is sex-dependent with females gaining the most benefit. Whether Apc Min/+ mice have a similar sex-dependent response to chronic mTOR inhibition is not known.

Methods: To address this knowledge gap and gain deeper insight into how chronic mTOR inhibition prevents intestinal polyposis, we compared male and female Apc Min/+ mice responses to chronic treatment with a rapamycin-containing diet. Animals were fed a diet containing either 42 ppm microencapsulate rapamycin or empty capsules, one group was used to determine lifespan and a second group with similar treatment was harvested at 16 weeks of age for cross-sectional studies.

Results: We found that the survival of males is greater than females in this setting (P < 0.0197). To explore the potential basis for this difference we analyzed factors affected by chronic rapamycin. Immunoblot assays showed that males and females exhibited approximately the same level of mTORC1 inhibition using phosphorylation of ribosomal protein S6 (rpS6) as an indirect measure. Immunohistochemistry assays of rpS6 phosphorylation showed that rapamycin reduction of mTORC1 activity was on the same level, with the most prominent difference being in intestinal crypt Paneth cells in both sexes. Chronic rapamycin also reduced crypt depths in both male and female Apc Min/+ mice (P < 0.0001), consistent with reduced crypt epithelial cell proliferation. Finally, chronic rapamycin prevented anemia equally in males and females.

Conclusions: In males and females, these findings link rapamycin-mediated intestinal polyposis prevention with mTORC1 inhibition in Paneth cells and concomitant reduced epithelial cell proliferation.

Keywords: Paneth cells; Rapamycin; crypt stem cells; mTORC1; polyposis; small intestine.


Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease

Chris E Shannon, Mukundan Ragavan, Juan Pablo Palavicini, Marcel Fourcaudot, Terry M Bakewell, Ivan A Valdez, Iriscilla Ayala, Eunsook S Jin, Muniswamy Madesh, Xianlin Han, Matthew E Merritt, Luke Norton
Mol Metab. 2021 Mar:45:101154. doi: 10.1016/j.molmet.2020.101154. Epub 2020 Dec 23.

Abstract:

Objective: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.

Methods: Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches. Mechanistic studies of pioglitazone action were performed in isolated primary hepatocytes, whilst molecular hepatic lipid species were profiled using shotgun lipidomics.

Results: Livers from obese, insulin-resistant mice displayed augmented mitochondrial content and increased tricarboxylic acid cycle (TCA) cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPARγ activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides, or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization.

Conclusion: Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.

Keywords: Cardiolipin; Insulin resistance; Metabolic liver disease; Mitochondria; Pyruvate dehydrogenase; Thiazolidinedione.