Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Spanos, Christos; Maldonado, Elaina M.; Fisher, Ciarán; Leenutaphong, Petchpailin; Oviedo‐Orta, Ernesto; Windridge, David; Salguero, Francisco J.; Bermúdez-Fajardo, Alexandra; Weeks, Mark E.; Evans, Caroline; Corfe, Bernard M.; Rabbani, Naila; Thornalley, Paul J.; Miller, Michael H.; Wang, Huan; Dillon, John; Quaglia, Alberto; Dhawan, Anil; Fitzpatrick, Emer; Moore, J. Bernadette

doi:10.1186/s12953-018-0131-y

Cited by 24 publications

(27 citation statements)

References 62 publications

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“…3c) and lQTLs for hepatic triacylglycerol species, whereas GLO1 protein positively correlated with nine individual triacylglycerol species in the liver (Supplementary Table 11). GLO1 was recently identified in genome-wide association studies to be strongly associated with coronary artery disease and non-alcoholic fatty liver disease 35,36 and therefore our data implicate GLO1 as a causal regulator of acylglycerol metabolism with potential links to cardiometabolic disease.…”

Section: Genetic Regulation Of Protein and Lipid Abundancesupporting

confidence: 63%

An integrative systems genetic analysis of mammalian lipid metabolism

Parker

Calkin

Seldin

et al. 2019

Nature

109

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Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity. There is an increasingly urgent need to understand the causal factors that contribute to excess lipid accumulation in the liver known as hepatosteatosis, and an equally important need to discover biomarkers and interventions for its early diagnosis and treatment. A major proportion of current and predicted global health burden stems from conditions in which hepatosteatosis is an underlying pathology 1. Defining the mechanisms that causally influence hepatosteatosis has historically proven challenging, largely owing to an ill-defined interaction between genetic and environmental factors 2. This, together with the insufficient ability for standard genome-wide association studies to capture the effect of environment on complex traits, probably explains why only a small fraction of the estimated 30% heritability for hepatosteatosis has been assigned to specific gene variants 3. Genetic reference panels (GRPs) have become a more tractable way of studying the influence of genetics and environment on complex traits, because unlike studies in humans, GRPs allow for accurate control of environment as well as access to critical metabolic tissues. Importantly, integrating intermediate phenotypes such as transcriptomics, Parker et al.

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Section: Genetic Regulation Of Protein and Lipid Abundancesupporting

confidence: 63%

An integrative systems genetic analysis of mammalian lipid metabolism

Parker

Calkin

Seldin

et al. 2019

Nature

109

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“…It is therefore important to explore not only the ability of hepatocytes to utilise sugars, but also their subsequent conversion into lipid. As triacylglycerol (TAG) is the predominate lipid species within the neutral lipid core of macrovesicular droplets, 30 the in silico model was then used to investigate the influence of monosaccharide type on TAG metabolism. TAG production (reaction ID: r1223) was set as the objective function and dFVA was used to explore the maximal and minimal TAG production possible for a given monosaccharide.…”

Section: Resultsmentioning

confidence: 99%

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

et al. 2018

Self Cite

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Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD.

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“…Its absence predisposes to metabolic syndrome (e.g., Alzheimer's disease, atherosclerosis, and obesity) and might be associated with NAFLD [ 27 ]. Therefore, ApoE −/− mice have been extensively employed as models for metabolic syndrome and NAFLD in recent years [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE^−/− Mice

Liu

et al. 2018

Oxidative Medicine and Cellular Longevity

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Diets containing various docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) ratios protect against liver damage in mice fed with a high-fat diet (HFD). However, it is unclear whether these beneficial roles of DHA and EPA are associated with alterations of fatty acid (FA) composition in the liver. This study evaluated the positive impacts of n-6/n-3 polyunsaturated fatty acids (PUFAs) containing different DHA/EPA ratios on HFD-induced liver disease and alterations of the hepatic FA composition. ApoE−/− mice were fed with HFDs with various ratios of DHA/EPA (2 : 1, 1 : 1, and 1 : 2) and an n-6/n-3 ratio of 4 : 1 for 12 weeks. After treatment, the serum and hepatic FA compositions, serum biochemical parameters, liver injury, and hepatic lipid metabolism-related gene expression were determined. Our results demonstrated that dietary DHA/EPA changed serum and hepatic FA composition by increasing contents of n-6 and n-3 PUFAs and decreasing amounts of monounsaturated fatty acids (MUFAs) and the n-6/n-3 ratio. Among the three DHA/EPA groups, the DHA/EPA 2 : 1 group tended to raise n-3 PUFAs concentration and lower the n-6/n-3 ratio in the liver, whereas DHA/EPA 1 : 2 tended to raise n-6 PUFAs concentration and improve the n-6/n-3 ratio. DHA/EPA supplementation reduced the hepatic impairment of lipid homeostasis, oxidative stress, and the inflammatory responses in HFD-fed mice. The DHA/EPA 2 : 1 group had lower serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol and higher levels of adiponectin than HFD group. The DHA/EPA 1 : 2 group had elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, without significant change the expression of genes for inflammation or hepatic lipid metabolism among the three DHA/EPA groups. The results suggest that DHA/EPA-enriched diet with an n-6/n-3 ratio of 4 : 1 may reverse HFD-induced nonalcoholic fatty liver disease to some extent by increasing n-6 and n-3 PUFAs and decreasing the amount of MUFAs and the n-6/n-3 ratio.

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Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Cited by 24 publications

References 62 publications

An integrative systems genetic analysis of mammalian lipid metabolism

An integrative systems genetic analysis of mammalian lipid metabolism

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE^−/− Mice

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Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Cited by 24 publications

References 62 publications

An integrative systems genetic analysis of mammalian lipid metabolism

An integrative systems genetic analysis of mammalian lipid metabolism

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE−/− Mice

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Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE^−/− Mice