Changes in the hepatic mitochondrial and membrane proteome in mice fed a non-alcoholic steatohepatitis inducing diet

Thomas, Anja; Klein, Matthias S.; Stevens, Axel Peter; Reinders, Yvonne; Hellerbrand, Claus; Dettmer, Katja; Gronwald, Wolfram; Oefner, Peter J.; Reinders, Jörg

doi:10.1016/j.jprot.2012.12.027

Cited by 22 publications

(21 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the second-ranked upregulated gene, METTL7B , has not been comprehensively studied in the context of the vertebrate brain. METTL7B , which is predominantly expressed in liver (Uhlen et al, 2015), encodes a membrane protein associated with endoplasmic reticulum (ER) and lipid droplets, and, by amino acid sequence homology, is predicted to belong to the protein methyltransferase superfamily (Turro et al, 2006; Thomas et al, 2013). We confirmed that at the RNA and protein level, METTL7B is enriched in the adult human hippocampus (Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Franjic

Choi

Škarica

et al. 2020

Preprint

View full text Add to dashboard Cite

RESULTS 104Transcriptomic diversity of hippocampal and entorhinal cells 105 To survey the transcriptomic diversity and functional specification of the mesial temporal 106 cortex, we used snRNA-seq to profile five subregions of the hippocampal-entorhinal system 107 6 collected from fresh frozen postmortem brains of clinically unremarkable human donors. These 108 specimens were selected from a larger pool of postmortem human brains based on the quality 109 of isolated nuclei and RNA. Taking into consideration dramatic cytoarchitectonic variations, 110 we microdissected the hippocampal formation (DG, CA2-4, CA1, and subiculum) and EC for 111 a total of five subregions (Fig. 1A). 112 Unbiased isolation of nuclei using our previously described protocol (Li et al., 2018; 113 Zhu et al., 2018) followed by snRNA barcoding, cDNA sequencing and quality filtering yielded 114 108,315 high-quality single-nucleus profiles from all five subregions ( Fig. 1A, S1A-D). 115 Analysis of the expression of genes known to be enriched in major cell subpopulations 116 suggested these included 44,697 neurons, of which 35,768 (80.02%) were glutamatergic 117 excitatory neurons (expressing the gene encoding the vesicular glutamate transporter SLC17A7) 118 and 8,929 (19.98%) were GABAergic inhibitory neurons (expressing the gene encoding the 119 GABA synthesis enzyme GAD1), reflecting the expected 80:20 ratio of these populations. In 120 addition, we identified 63,618 (58.73% of the total population) non-neuronal cells. 121 We next analyzed the transcriptomes of those nuclei on the Uniform Manifold 122 Approximation and Projection (UMAP) layout representing their similarities at cellular 123 granularity ( Fig. 1B-D). Iterative clustering defined 69 transcriptomically distinct cell clusters 124 representing presumptive cell types across all individuals (donors). These transcriptomically 125 diverse subpopulations were organized into a dendrogramatic taxonomy reflecting their gene 126 expression patterns and were subsequently assigned identities commensurate with predicted cell 127 types. This allowed us to identify 26 subtypes of excitatory neurons (Fig. 1E and S2A-B), 23 128 inhibitory neuron subtypes ( Fig. 1E and S2C-D), and 20 non-neuronal cell types and subtypes 129 ( Fig. 1E and S2E-F). Similar single nucleus approaches applied to human neocortical samples 130 7 yielded comparable numbers and distributions of cell populations in medial temporal gyrus 131 (MTG) (Hodge et al., 2019)and dorso-lateral prefrontal cortex (dlPFC) (Li et al., 2018)(Fig. 132 S1E-F). 133Within excitatory neuron subtypes, we found marked transcriptional diversity that 134 reflects differences in the cytoarchitectonic organization among the subregions of the HIP (DG, 135 CA2-4, CA1, and subiculum) and EC (Fig. 1E). For example, in addition to ADCYAP1-136 expressing mossy cells in DG, we found three distinct subclusters of PROX1-expressing granule 137 cells. We also identified excitatory neurons in CA1 and CA2-4 that could be deconstructe...

show abstract

Section: Resultsmentioning

confidence: 99%

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Franjic

Choi

Škarica

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Afterward, all visible bands were excised and subjected to in-gel-digestion as published previously (27). Resulting peptides were used for nano-LC-MS/MS analysis on a TripleTOF 5600+ mass spectrometer (Sciex, Darmstadt, Germany) as published previously (24).…”

Section: Methodsmentioning

confidence: 99%

Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

et al. 2016

View full text Add to dashboard Cite

The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.

show abstract

“…; Bondia‐Pons et al., ; Kirpich et al., ; Oh et al., ; Rubio‐Aliaga et al., ; Almon et al., ; Midha et al., ; Kim et al., ; Benard et al., ; Cheng et al., ). This led to an emerging interest in the role of mitochondria in NAFLD and nonalcoholic steatohepatitis (Guo et al., ; Thomas et al., ; Li et al., ; Nesteruk et al., ). Most of these studies investigated the development of fatty liver in mice at juvenile life stages and clearly demonstrate that fat accumulation in adolescent mice can be induced by high fat diet depending on the fat source and the duration of feeding (Satapati et al., ; Fontana et al., ; Ludwig et al., ; Nakamura and Terauchi, ).…”

Section: Introductionmentioning

confidence: 99%

“…Several global omics-based studies have addressed the molecular aspects of fatty liver development in dietinduced obese rodent models and diabetic mice (Baiges et al, 2010;Xie et al, 2010;Zhang et al 2010;Bondia-Pons et al, 2011;Kirpich et al, 2011;Oh et al, 2011;Rubio-Aliaga et al, 2011;Almon et al, 2012;Midha et al, 2012;Kim et al, 2013;Benard et al, 2016;Cheng et al, 2016). This led to an emerging interest in the role of mitochondria in NAFLD and nonalcoholic steatohepatitis (Guo et al, 2013;Thomas et al, 2013;Li et al, 2014;Nesteruk et al, 2014). Most of these studies investigated the development of fatty liver in mice at juvenile life stages and clearly demonstrate that fat accumulation in adolescent mice can be induced by high fat diet depending on the fat source and the duration of feeding (Satapati et al, 2012;Fontana et al, 2013;Ludwig et al, 2013;Nakamura and Terauchi, 2013).…”

Section: Introductionmentioning

confidence: 99%

Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice

et al. 2016

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial‐derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle‐aged mice. Susceptibility to diet‐induced obesity increased with age. Young adult and middle‐aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age‐related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat‐fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid‐derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet‐induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized.

show abstract

Changes in the hepatic mitochondrial and membrane proteome in mice fed a non-alcoholic steatohepatitis inducing diet

Cited by 22 publications

References 76 publications

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice

Contact Info

Product

Resources

About