Metabolism
Abstract
Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome–derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1–mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome–derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe–dependent metabolism, as well as interorganismal communication between the host and microbiome.
Authors
Jeffry C. Granados, Vladimir Ermakov, Koustav Maity, David R. Vera, Geoffrey Chang, Sanjay K. Nigam
Abstract
The G protein–coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor–associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.
Authors
Adelaide Bernard, Irene Ojeda Naharros, Xinyu Yue, Francois Mifsud, Abbey Blake, Florence Bourgain-Guglielmetti, Jordi Ciprin, Sumei Zhang, Erin McDaid, Kellan Kim, Maxence V. Nachury, Jeremy F. Reiter, Christian Vaisse
Abstract
Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contributed to lipotoxicity in obesity-related kidney disease, both in humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here we found that palmitic acid (PA) strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway in a Rag GTPase–dependent manner, although these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. Proximal tubular epithelial cell (PTEC)-specific Tfeb-deficient mice fed a high-fat diet (HFD) exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, which help reduce MLB accumulation in PTECs. Furthermore, HFD-fed PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia–reperfusion. Finally, higher body mass index was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubules of chronic kidney disease patients. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.
Authors
Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of SREBP (sterol regulatory element binding protein) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immuno-metabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in Broncho Alveolar Lavage (BAL) cells isolated from IPF patients compared to healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 Peptide Nucleic Acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. Together, these studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a novel therapeutic approach to treat this disease.
Authors
Farida Ahangari, Nathan L. Price, Shipra Malik, Maurizio Chioccioli, Thomas Bärnthaler, Taylor S. Adams, Jooyoung Kim, Sai Pallavi Pradeep, Shuizi Ding, Carlos Cosme Jr, Kadi-Ann S. Rose, John E. McDonough, Nachelle R. Aurelien, Gabriel Ibarra, Norihito Omote, Jonas C. Schupp, Giuseppe DeIuliis, Julian A. Villalba Nunez, Lokesh Sharma, Changwan Ryu, Charles S. Dela Cruz, Xinran Liu, Antje Prasse, Ivan Rosas, Raman Bahal, Carlos Fernandez-Hernando, Naftali Kaminski
Abstract
Activin receptor-like kinase 7 (ALK7) is a type I receptor in the transforming growth factor-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist-to-hip ratios and resistance to development of diabetes. The present study found that treatment with a neutralizing monoclonal antibody against ALK7 causes a substantial loss (40-60%) of adipose mass and improves glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and O2 consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term antibody treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and subsequently interleukin-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
Authors
Min Zhao, Katsuhide Okunishi, Yun Bu, Osamu Kikuchi, Hao Wang, Tadahiro Kitamura, Tetsuro Izumi
Abstract
Central integration of peripheral appetite-regulating signals ensures maintenance of energy homeostasis. Thus, plasticity of circulating molecule access to neuronal circuits involved in feeding behavior plays a key role in the adaptive response to metabolic changes. However, the mechanisms involved remain poorly understood despite their relevance for therapeutic development. Here, we investigated the role of median eminence mural cells, including smooth muscle cells and pericytes, in modulating gut hormone effects on orexigenic/anorexigenic circuits. We found that conditional activation of median eminence vascular cells impinged on local blood flow velocity, and altered ghrelin-stimulated food intake by delaying ghrelin access to target neurons. Thus, activation of median eminence vascular cells modulates food intake in response to peripheral ghrelin by reducing local blood flow velocity and access to the metabolic brain.
Authors
Nicola Romanò, Chrystel Lafont, Pauline Campos, Anne Guillou, Tatiana Fiordelisio, David J. Hodson, Patrice Mollard, Marie Schaeffer
Abstract
Elevated circulating dipeptidyl-peptidase 4 is a biomarker for liver disease, but its involvement in gluconeogenesis and in metabolic-associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of whole body Dpp4-/- displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice fed with HFHC diet, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR > 2) who underwent direct antiviral treatment (with or without ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.
Authors
Natasha A. Trzaskalski, Branka Vulesevic, My-Anh Nguyen, Natasha Jeraj, Evgenia Fadzeyeva, Nadya M. Morrow, Cassandra A.A. Locatelli, Nicole Travis, Antonio A. Hanson, Julia R.C. Nunes, Conor O'Dwyer, Jelske N. Van der Veen, Ilka Lorenzen-Schmidt, Rick Seymour, Serena M. Pulente, Andrew C. Clément, Angela M. Crawley, René L. Jacobs, Mary-Anne Doyle, Curtis L. Cooper, Kyoung-Han Kim, Morgan D. Fullerton, Erin E. Mulvihill
Abstract
Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. Herein, we found that carboxylesterase 1 (CES1) was expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, LC-MS/MS and lipidomic analyses revealed that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Consistently, clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the “CES1-PPARα/γ-SCD” axis sensitized HCC cells to cisplatin treatment. As a demonstration, the growth of HCC xenograft tumors in NU/J mice was potently limited by co-administration of cisplatin and CES1 inhibition. Our results suggest that CES1 is a promising therapeutic target for HCC treatment.
Authors
Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L. Eckel-Mahan, Philip L. Lorenzi, Richard Lehner, Kai Sun
Abstract
Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
Authors
Ashot Sargsyan, Ludivine Doridot, Sarah Anissa Hannou, Wenxin Tong, Harini Srinivasan, Rachael Ivison, Ruby Monn, Henry H. Kou, Jonathan M. Haldeman, Michelle Arlotto, Phillip J. White, Paul A. Grimsrud, Inna Astapova, Linus T.-Y. Tsai, Mark A. Herman
Abstract
BACKGROUND. At the onset of exercise, the speed at which PCr decreases towards a new steady state (PCr on-kinetics), reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal muscle. We hypothesized that PCr on-kinetics are slower in metabolically compromised and older individuals, and associated with low carnitine acetyl-transferase (CrAT) protein activity and compromised physical function. METHODS. We applied 31P-Magnetic Resonance Spectroscopy (MRS) to assess PCr on-kinetics in two cohorts of human volunteers. Cohort 1: patients with type 2 diabetes, obese, lean trained and untrained individuals. Cohort 2: young and older individuals with normal physical activity and older trained. Previous results of CrAT protein activity and acetylcarnitine content in muscle tissue were used to explore the underlying mechanisms of PCr on-kinetics, along with various markers of physical function. RESULTS. PCr on-kinetics were significantly slower in metabolically compromised and older individuals (indicating mitochondrial inertia) as compared to young and older trained volunteers, regardless of in vivo skeletal muscle oxidative capacity (P<0.001). Mitochondrial inertia correlated with reduced CrAT protein activity, low acetylcarnitine content and also with functional outcomes (P<0.001). CONCLUSION. PCr on-kinetics are significantly slower in metabolically compromised and older individuals with normal physical activity compared to young and older trained, regardless of in vivo skeletal muscle oxidative capacity, indicating greater mitochondrial inertia. Thus, PCr on-kinetics are a currently unexplored signature of skeletal muscle mitochondrial metabolism, tightly linked to functional outcomes. Skeletal muscle mitochondrial inertia might emerge as a target of intervention to improve physical function. TRIAL REGISTRATION. clinicaltrials.gov: NCT01298375 and clinicaltrials.gov: NCT03666013. FUNDING. R.M and M.H were granted with an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). V.S was supported by an ERC staring grant (Grant no. 759161) "MRS in Diabetes".
Authors
Rodrigo F. Mancilla, Lucas Lindeboom, Lotte Grevendonk, Joris Hoeks, Timothy R. Koves, Deborah M. Muoio, Patrick Schrauwen, Vera Schrauwen-Hinderling, Matthijs K.C. Hesselink
No posts were found with this tag.
