The common patatin-like phospholipase domain–containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low–density lipoproteins (VLDL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.
Panu K. Luukkonen, Auli Nick, Maarit Hölttä-Vuori, Christoph Thiele, Elina Isokuortti, Susanna Lallukka-Brück, You Zhou, Antti Hakkarainen, Nina Lundbom, Markku Peltonen, Marju Orho-Melander, Matej Orešič, Tuulia Hyötyläinen, Leanne Hodson, Elina Ikonen, Hannele Yki-Järvinen
Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyte Jak2 (JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyte Jak2 (JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here suggests a attention be paid towards inhibition of adipocyte GH signaling as a therapeutic target of metabolic liver disease.
Kevin C. Corbit, Camella G. Wilson, Dylan Lowe, Jennifer L. Tran, Nicholas B. Vera, Michelle Clasquin, Aras N. Mattis, Ethan J. Weiss
Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild type and diabetic (leptin receptor deficient - db/db) mice. Mice treated with tesaglitazar-containing chow or high fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1-/- mice. Our data shows that drugs, which activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance likely due to competition between these two transcription factors.
Charikleia Kalliora, Ioannis D. Kyriazis, Shin-ichi Oka, Melissa J. Lieu, Yujia Yue, Estela Area-Gomez, Christine J. Pol, Ying Tian, Wataru Mizushima, Adave Chin, Diego Scerbo, P. Christian Schulze, Mete Civelek, Junichi Sadoshima, Muniswamy Madesh, Ira J. Goldberg, Konstantinos Drosatos
Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.
Yichen Wang, Heather Zhou, Oksana Palyha, James Mu
Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to–bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.
Mathilde Mouchiroud, Étienne Camiré, Manal Aldow, Alexandre Caron, Éric Jubinville, Laurie Turcotte, Inès Kaci, Marie-Josée Beaulieu, Christian Roy, Sébastien M. Labbé, Thibault V. Varin, Yves Gélinas, Jennifer Lamothe, Jocelyn Trottier, Patricia L. Mitchell, Frédéric Guénard, William T. Festuccia, Philippe Joubert, Christopher F. Rose, Constantine J. Karvellas, Olivier Barbier, Mathieu C. Morissette, André Marette, Mathieu Laplante
BACKGROUND. Acute graft-versus-host disease (aGvHD) is a major factor that limits the successful outcomes of allogeneic hematopoietic cell transplantation (alloHSCT). Currently there are few validated biomarkers that can help predict the risk of aGvHD in clinical settings. METHODS. We performed an integrated metabolomics and transcriptomics study and identified biomarkers that distinguish alloHSCT recipients with aGvHD from alloHSCT recipients without aGvHD in two separate cohorts. RESULTS. Pathway analysis of 38 significantly altered metabolites and 1148 differentially expressed genes uncovered a distinctly altered glycerophospholipid (GPL) metabolism network. Subsequently, we developed an aGvHD risk score (GRS) based on 5 metabolites markers from GPL metabolism to predict the risk of aGvHD. GRS showed a positive predictive value of 92.2% and 89.6% in the training and validation cohorts, respectively. In addition, high GRS was correlated with poor overall survival. Gene expressions of GPL-related lipases were significantly altered in aGvHD samples, leading to dysregulated GPLs. CONCLUSIONS. Using integrative “Omic” analysis, we unraveled a comprehensive view of the molecular perturbations underlying the pathogenesis of aGvHD. Our work represents an initial investigation of a unique metabolic and transcriptomic network that may help identify aGvHD at an early stage and facilitate preemptive therapy. FUNDING. National Natural Science Foundation of China (NSFC; 81530047, 81870143, 81470321, 81770160, 81270567, 81270638, 81573396, 81703674). Shanghai Sailing Program from Science and Technology Commission Shanghai Municipality (17YF1424700). Scholarship from Shanghai Municipal Health and Family Planning Commission (2017BR012). Special Clinical Research in Health Industry in Shanghai (20184Y0054).
Yue Liu, Aijie Huang, Qi Chen, Xiaofei Chen, Yang Fei, Xiaoming Zhao, Weiping Zhang, Zhanying Hong, Zhenyu Zhu, Jianmin Yang, Yifeng Chai, Jianmin Wang, Xiaoxia Hu
Mitochondrial dysfunction characterizes many rare and common age-associated diseases. The biochemical consequences, underlying clinical manifestations, and potential therapeutic targets, remain to be better understood. We tested the hypothesis that lipid dyshomeostasis in mitochondrial disorders goes beyond mitochondrial fatty acid β-oxidation, particularly in liver. This was achieved using comprehensive untargeted and targeted lipidomics in a case-control cohort of patients with Leigh syndrome French-Canadian variant (LSFC), a mitochondrial disease caused by mutations in LRPPRC, and in mice harboring liver-specific inactivation of Lrpprc (H-Lrpprc–/–). We discovered a plasma lipid signature discriminating LSFC patients from controls encompassing lower levels of plasmalogens and conjugated bile acids, which suggest perturbations in peroxisomal lipid metabolism. This premise was reinforced in H-Lrpprc–/– mice, which compared with littermates recapitulated a similar, albeit stronger peroxisomal metabolic signature in plasma and liver including elevated levels of very-long-chain acylcarnitines. These mice also presented higher transcript levels for hepatic markers of peroxisome proliferation in addition to lipid remodeling reminiscent of nonalcoholic fatty liver diseases. Our study underscores the value of lipidomics to unveil unexpected mechanisms underlying lipid dyshomeostasis ensuing from mitochondrial dysfunction herein implying peroxisomes and liver, which likely contribute to the pathophysiology of LSFC, but also other rare and common mitochondrial diseases.
Matthieu Ruiz, Alexanne Cuillerier, Caroline Daneault, Sonia Deschênes, Isabelle Robillard Frayne, Bertrand Bouchard, Anik Forest, Julie Thompson Legault, The LSFC Consortium, Frederic M. Vaz, John D. Rioux, Yan Burelle, Christine Des Rosiers
We determined which metabolic pathways are activated by hypoxia-inducible factor 1–mediated (HIF-1–mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre–knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.
Charandeep Singh, George Hoppe, Vincent Tran, Leah McCollum, Youstina Bolok, Weilin Song, Amit Sharma, Henri Brunengraber, Jonathan E. Sears
Glucagon and insulin are commonly believed to have counteracting effects on blood glucose levels. However, recent studies have demonstrated that glucagon has a physiologic role to activate β-cells and enhance insulin secretion. To date, the actions of glucagon have been studied mostly in fasting or hypoglycemic states, yet it is clear that mixed-nutrient meals elicit secretion of both glucagon and insulin, suggesting that glucagon also contributes to glucose regulation in the postprandial state. We hypothesized that the elevated glycemia seen in the fed state would allow glucagon to stimulate insulin secretion and reduce blood glucose. In fact, exogenous glucagon given under fed conditions did robustly stimulate insulin secretion and lower glycemia. Exogenous glucagon given to fed Gcgr:Glp1rβcell-/- mice failed to stimulate insulin secretion or reduce glycemia, demonstrating the importance of an insulinotropic glucagon effect. The action of endogenous glucagon to reduce glycemia in the fed state was tested with administration of alanine, a potent glucagon secretagogue. Alanine raised blood glucose in fasted WT mice or fed Gcgr:Glp1rβcell-/- mice, conditions where glucagon is unable to stimulate β-cell activity. However, alanine given to fed WT mice produced a decrease in glycemia, along with elevated insulin and glucagon levels. Overall, our data support a model in which glucagon serves as an insulinotropic hormone in the fed state and complements rather than opposes insulin action to maintain euglycemia.
Megan E. Capozzi, Jacob B. Wait, Jepchumba Koech, Andrew N. Gordon, Reilly W. Coch, Berit Svendsen, Brian Finan, David A. D'Alessio, Jonathan E. Campbell
The synthesis of lipid and sterol species through de novo lipogenesis (DNL) is regulated by two functionally overlapping but distinct transcription factors: the sterol regulatory element-binding proteins (SREBPs) and carbohydrate response element binding protein (ChREBP). ChREBP is considered to be the dominant regulator of DNL in adipose tissue (AT); however, the SREBPs are highly expressed and robustly regulated in adipocytes, suggesting that the model of AT DNL may be incomplete. Here we describe a new mouse model of inducible, adipocyte-specific overexpression of the insulin-induced gene 1 (Insig1), a negative regulator of SREBP transcriptional activity. Contrary to convention, Insig1 overexpression did block AT lipogenic gene expression. However, this was immediately met with a compensatory mechanism triggered by redox activation of mTORC1 to restore SREBP1 DNL gene expression. Thus, we demonstrate that SREBP1 activity sustains adipocyte lipogenesis, a conclusion that has been elusive due to the constitutive nature of current mouse models.
Clair Crewe, Yi Zhu, Vivian A. Paschoal, Nolwenn Joffin, Alexandra L. Ghaben, Ruth Gordillo, Da Young Oh, Guosheng Liang, Jay D. Horton, Philipp E. Scherer
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