scholarly journals Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis

2018 ◽  
Vol 164 (2) ◽  
pp. 428-438 ◽  
Author(s):  
Hui Li ◽  
Erica Toth ◽  
Nathan J Cherrington
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Protein Level ◽  
Mrna Levels ◽  
Alcohol Metabolism ◽  
Aldh Activity ◽  
Nonalcoholic Fatty Liver ◽  
Protein Levels ◽  
Protein Adduct ◽  
And Function ◽  
Adh Activity

Abstract Alcohol metabolism is a well-characterized biological process that is dominated by the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) families. Nonalcoholic steatohepatitis (NASH) is the advanced inflammatory stage of nonalcoholic fatty liver disease (NAFLD) and is known to alter the metabolism and disposition of numerous drugs. The purpose of this study was to investigate the alterations in alcohol metabolism processes in response to human NASH progression. Expression and function of ADHs, ALDHs, and catalase were examined in normal, steatosis, NASH (fatty) and NASH (not fatty) human liver samples. ALDH4A1 mRNA was significantly decreased in both NASH groups, while no significant changes were observed in the mRNA levels of other alcohol-related enzymes. The protein levels of ADH1A, ADH1B, and ADH4 were each decreased in the NASH groups, which was consistent with a decreased overall ADH activity. The protein level of ALDH2 was significantly increased in both NASH groups, while ALDH1A1 and ALDH1B1 were only decreased in NASH (fatty) samples. ALDH activity represented by oxidation of acetaldehyde was decreased in the NASH (fatty) group. The protein level of catalase was decreased in both NASH groups, though activity was unchanged. Furthermore, the significant accumulation of 4-hydroxynonenal protein adduct in NASH indicated significant oxidative stress and a potential reduction in ALDH activity. Collectively, ADH and ALDH expression and function are profoundly altered in the progression of NASH, which may have a notable impact on ADH- and ALDH-associated cellular metabolism processes and lead to significant alterations in drug metabolism mediated by these enzymes.

Differential regulation of G protein expression in rat hearts exposed to chronic hypoxia

1995 ◽  
Vol 269 (6) ◽  
pp. H1865-H1873 ◽  
Author(s):  
R. Kacimi ◽  
J. M. Moalic ◽  
A. Aldashev ◽  
D. E. Vatner ◽  
J. P. Richalet ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Functional Activity ◽  
Protein Level ◽  
Chronic Hypoxia ◽  
Mrna Level ◽  
Mrna Levels ◽  
Protein Levels ◽  
Rat Hearts ◽  
And Function

Chronic hypoxia impairs adrenergic responsiveness. A modulation of Gs and/or G1 protein alpha-subunits may be associated with the downregulation of the beta-adrenergic receptors previously found in chronic hypoxia. G protein gene expression and protein level and function in rat hearts exposed to a 30-day hypobaric chronic hypoxia were compared with control rat hearts. No change was observed in G alpha s mRNA levels in either right or left ventricles. In right ventricles, mRNA levels of G alpha i-2 increased by 40% (P < 0.05), but not in left ventricles. In both left and right ventricles, chronic hypoxia did not modify G alpha i-2 and G alpha s protein amounts, but significantly decreased functional activity of G alpha s. In conclusion, gene expression, protein levels of G alpha s and G alpha i-2, and activity of G alpha s do not change in parallel fashion with chronic hypoxia. In chronic hypoxic right ventricles, although the mRNA level of G alpha i-2 is increased, the protein level is unchanged. One potential mechanism of desensitization to catecholamines in chronic hypoxia appears to involve a decreased functional activity of G alpha s in spite of normal mRNA and protein levels

scholarly journals Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Disease Model ◽  
Neuronal Loss ◽  
Mrna Levels ◽  
Gene Therapies ◽  
Protein Levels ◽  
Dopaminergic Systems ◽  
And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

scholarly journals Circulating Levels of Pro-Neurotensin and Its Relationship with Nonalcoholic Steatohepatitis and Hepatic Lipid Metabolism

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 373
Author(s):  
Beatriz Villar ◽  
Laia Bertran ◽  
Carmen Aguilar ◽  
Jessica Binetti ◽  
Salomé Martínez ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Lipid ◽  
Normal Liver ◽  
Normal Weight ◽  
Published Data ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Liver Lipid Metabolism

Recent studies suggest a link between pro-neurotensin (pro-NT) and nonalcoholic fatty liver disease (NAFLD), but the published data are conflicting. Thus, we aimed to analyze pro-NT levels in women with morbid obesity (MO) and NAFLD to investigate if this molecule is involved in NAFLD and liver lipid metabolism. Plasma levels of pro-NT were determined in 56 subjects with MO and 18 with normal weight (NW). All patients with MO were subclassified according to their liver histology into the normal liver (NL, n = 20) and NAFLD (n = 36) groups. The NAFLD group had 17 subjects with simple steatosis (SS) and 19 with nonalcoholic steatohepatitis (NASH). We used a chemiluminescence sandwich immunoassay to quantify pro-NT in plasma and RT-qPCR to evaluate the hepatic mRNA levels of several lipid metabolism-related genes. We reported that pro-NT levels were significantly higher in MO with NAFLD than in MO without NAFLD. Additionally, pro-NT levels were higher in NASH patients than in NL. The hepatic expression of lipid metabolism-related genes was found to be altered in NAFLD, as previously reported. Additionally, although pro-NT levels correlated with LDL, there was no association with the main lipid metabolism-related genes. These findings suggest that pro-NT could be related to NAFLD progression.

scholarly journals The mechanism of increased intestinal palmitic acid absorption and its impact on hepatic stellate cell activation in nonalcoholic steatohepatitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masakazu Hanayama ◽  
Yasunori Yamamoto ◽  
Hiroki Utsunomiya ◽  
Osamu Yoshida ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Portal Vein ◽  
Palmitic Acid ◽  
Intestinal Absorption ◽  
Nonalcoholic Steatohepatitis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Chylomicron Formation

AbstractDietary palmitic acid (PA) promotes liver fibrosis in patients with nonalcoholic steatohepatitis (NASH). Herein, we clarified the intestinal absorption kinetics of dietary PA and effect of trans-portal PA on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in NASH. Blood PA levels after meals were significantly increased in patients with NASH compared to those in the control. Expression of genes associated with fat absorption and chylomicron formation, such as CD36 and MTP, was significantly increased in the intestine of NASH model rats compared with that in the controls. Plasma levels of glucagon-like peptide-2, involved in the upregulation of CD36 expression, were elevated in NASH rats compared with those in the controls. Furthermore, portal PA levels after meals in NASH rats were significantly higher than those in control and nonalcoholic fatty liver rats. Moreover, PA injection into the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs. Increased intestinal absorption of diet-derived PA was observed in NASH. Thus, the rapid increase in PA levels via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

scholarly journals DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα

2013 ◽  
Vol 451 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Claudia C. S. Chini ◽  
Carlos Escande ◽  
Veronica Nin ◽  
Eduardo N. Chini
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Clock Genes ◽  
Mrna Levels ◽  
Protein Levels ◽  
The Stability ◽  
And Function ◽  
Interfering Rna ◽  
In Cells

The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.

scholarly journals Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3382-3397 ◽  
Author(s):  
Frédéric M Vaz ◽  
John H McDermott ◽  
Mariëlle Alders ◽  
Saskia B Wortmann ◽  
Stefan Kölker ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Membrane Lipids ◽  
Cerebellar Atrophy ◽  
Global Developmental Delay ◽  
Mrna Levels ◽  
Spastic Paraplegia ◽  
Protein Levels ◽  
And Function ◽  
Lipid Abnormalities ◽  
The Brain

Abstract CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.

Abstract 19706: CD39/CD73 Pathway in End-stage Human Ischemic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tatiana Novitskaya ◽  
Yan Ru Su ◽  
Simon Maltais ◽  
Tarek S Absi ◽  
Richard J Gumina
Keyword(s):  
Protein Level ◽  
Ischemic Cardiomyopathy ◽  
Ischemia Reperfusion ◽  
Immunohistochemical Analysis ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Protein Levels ◽  
Left Ventricular Tissue ◽  
Ventricular Tissue ◽  
End Stage

Introduction: CD39 (ectonucleoside triphosphate diphosphohydrolase) is a nucleotidase expressed on endothelial cells, vascular smooth muscles cells, and leukocytes. CD39 plays a key role in vascular homeostasis, hydrolyzing extracellular ATP or ADP to AMP. CD73 (ecto-5’-nculeotidase) hydrolyzes AMP to adenosine. Both CD39 and CD73 are key modulators of purinergic signaling and have been shown to be important in ischemic preconditioning and ischemia reperfusion in animal models. Hypothesis: We hypothesized that the expression of the purine nucleotide-metabolizing pathway consisting of CD39 and CD73 in human hearts with ischemic cardiomyopathy is unregulated in response to ischemia. Methods: We compared the expression of CD39 and CD73 in left ventricular samples from patients with end-stage ischemic cardiomyopathy and normal hearts. Left ventricular tissue obtained from 7 end-stage ischemic cardiomyopathy hearts and 7 normal hearts not used for transplantation were homogenized and the levels of CD39 and CD73 mRNA were measured by qRT-PCR. Using the same tissue, immunoblot analysis for the protein level of CD39 and CD73 was conducted. Furthermore, immunohistochemical analysis of CD39 and CD73 expression was conducted on left ventricular tissue from the same subjects. Results: The total mRNA levels of CD39 and CD73 were increased in patients with end-stage ischemic cardiomyopathy. However, while there was a reduction in the total CD73 protein levels that did not reach significance, there was a marked reduction in the the total protein level of CD39 in ICM hearts (Figure). Immunohistochemical analysis demonstrated that the expression pattern of CD39 was significantly different in ICM hearts compared to normal hearts. Conclusions: These data provide important evidence that the extracellular nucleotide metabolizing pathway is altered in ICM. CD39 protein levels are significantly reduced in human end-stage ischemic cardiomyopathy.

scholarly journals Rapid Recapitulation of Nonalcoholic Steatohepatitis upon Loss of Host Cell Factor 1 Function in Mouse Hepatocytes

2018 ◽  
Vol 39 (5) ◽  
Author(s):  
Shilpi Minocha ◽  
Dominic Villeneuve ◽  
Viviane Praz ◽  
Catherine Moret ◽  
Maykel Lopes ◽  
...  
Keyword(s):  
Host Cell ◽  
Nonalcoholic Steatohepatitis ◽  
Genetically Engineered ◽  
Mouse Development ◽  
Linked Gene ◽  
Nonalcoholic Fatty Liver ◽  
Host Cell Factor ◽  
Mouse Hepatocytes ◽  
And Function ◽  
Host Cell Factor 1

ABSTRACT Host cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1, is an epigenetic coregulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knockout allele (called Hcfc1hepKO) to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1hepKO/Y males by 4 days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1-positive and -negative hepatocyte clusters is engineered. The livers with Hcfc1hepKO/Y hepatocytes displayed a 21- to 24-day terminal nonalcoholic fatty liver (NAFL), followed by nonalcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild NAFL development. Loss of HCF-1 led to loss of PGC1α protein, probably owing to its destabilization, and deregulation of gene expression, particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1hepKO/Y liver pathology. Thus, HCF-1 is essential for hepatocyte function, likely playing both transcriptional and nontranscriptional roles. These genetically engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution.

scholarly journals Pharmacodynamic Evaluation of the Gexia Zhuyu Decoction in the Treatment of NAFLD and the Molecular Mechanism Underlying the TRPM4 Pathway Regulation

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Yao-Wei Zhao ◽  
Jing Yang ◽  
Jie Niu ◽  
Tong Wang ◽  
Xin-Dan Liang ◽  
...  
Keyword(s):  
Liver Tissue ◽  
Molecular Mechanisms ◽  
Fibrous Tissue ◽  
Density Lipoprotein ◽  
Disease Stage ◽  
Mrna Levels ◽  
Drug Intervention ◽  
Nonalcoholic Fatty Liver ◽  
Protein Levels ◽  
Pathway Regulation

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome of abnormal lipid deposition in the liver mediated by nonalcohol intake. The Gexia Zhuyu decoction, a classic traditional Chinese medicine compound, is widely used in the clinical treatment of NAFLD. However, its specific efficacy and underlying mechanisms have not been elucidated yet. This study aimed to quantitatively evaluate the efficacy of the Gexia Zhuyu decoction using pharmacodynamics and to explore its molecular mechanisms in conjunction with proteomics. High-fat diets and methionine choline-deficient diets were used to induce various NAFLD progression stages in mouse models. The effects of oral Gexia Zhuyu decoction administration on NAFLD were evaluated by measuring the serum and liver indicators of the treated mice before and after drug intervention and by comparing the changes in liver tissue. Liver TRPM4 mRNA and protein levels were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively. Experimental data showed that serum ALT, AST, and liver triglyceride (TG) levels in each disease stage group of drug intervention mice decreased, and high-density lipoprotein (HDL) and superoxide dismutase (SOD) levels increased. Liver TG levels decreased after drug intervention in the liver fibrosis mice, but serum TG levels increased. Furthermore, cellular fatty changes, inflammatory changes, and fibrous tissue proliferation were all relieved. The TRPM4 protein and mRNA levels in the liver tissue were decreased, and the microRNA (miRNA)-24 expression was increased. The Gexia Zhuyu decoction has a clear therapeutic effect at each stage of NAFLD. It likely acts by altering miRNA-24 expression and regulating the target TRPM4 protein pathway to achieve NAFLD treatment.

scholarly journals Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease

2021 ◽  
Author(s):  
Fiona Dick ◽  
Ole-Bjørn Tysnes ◽  
Guido Werner Alves ◽  
Gonzalo S. Nido ◽  
Charalampos Tzoulis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Level ◽  
Spatial Separation ◽  
Healthy Ageing ◽  
Mrna Levels ◽  
Protein Levels ◽  
A Genome ◽  
Genes Encoding ◽  
Ageing Brain

AbstractThe correlation between mRNA and protein levels has been shown to decline in the ageing brain, possibly reflecting age-dependent changes in the proteostasis. It is thought that impaired proteostasis may be implicated in the pathogenesis of Parkinson’s disease (PD), but evidence derived from the patient brain is currently limited. Here, we hypothesized that if impaired proteostasis occurs in PD, this should be reflected in the form of altered correlation between transcriptome and proteome compared to healthy ageing.To test this hypothesis, we integrated transcriptomic data with proteomics from prefrontal cortex tissue of 17 PD patients and 11 demographically matched healthy controls and assessed gene-specific correlations between RNA and protein level. To control for the effects of ageing, brain samples from 4 infants were included in the analyses.In the healthy aged brain, we observed a genome-wide decreased correlation between mRNA and protein levels. Moreover, a group of genes encoding synaptic vesicle proteins exhibited inverse correlations. This phenomenon likely reflects the spatial separation of mRNA and protein into the neuronal soma and synapsis, respectively, commonly characterizing these genes. Most genes showed a significantly lower correlation between mRNA and protein levels in PD compared to neurologically healthy ageing, consistent with a proteome-wide decline in proteostasis. Genes showing an inverse correlation in PD were enriched for proteasome subunits, suggesting that these proteins show accentuated spatial separation of transcript and protein between the soma and axon/synapses in PD neurons. Moreover, the PD brain was characterized by increased positive mRNA-protein correlation for some genes encoding components of the mitochondrial respiratory chain, suggesting these may require tighter regulation in the face of mitochondrial pathology characterizing the PD brain.Our results are highly consistent with a proteome-wide impairment of proteostasis in the PD brain and strongly support the hypothesis that aberrant proteasomal function is implicated in the pathogenesis of PD. Moreover, our findings have important implications for the correct interpretation of differential gene expression studies in PD. In the presence of disease-specific altered coupling of transcriptome and proteome, measured differences in mRNA levels cannot be used to infer changes at the protein-level and should be supplemented with direct determination of proteins nominated by the analyses.

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