Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.
Mice overexpressing or deficient in hepatocyte miR-34a and control mice were fed a diet enriched in fats, cholesterol, and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression, and reversal of NAFLD was determined.
Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice and patients with non-alcoholic steatohepatitis (NASH), yet hepatocyte miR-34a's role in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.
Xu Y; Zhu Y; Hu S; Pan X; Bawa FC; Wang HH; Wang DQ; Yin L; Zhang Y
Molecular Metabolism
2021
2021-05-15
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Journal Article
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Assessment of chronic liver disease by multiparametric ultrasound: results from a private practice outpatient facility.
To assess chronic liver disease (CLD) using multiparametric US in a private practice setting in a cohort of patients with increased skin-to-liver distance.
110 consecutive patients with increased skin-to-liver distance scheduled for US assessment of CLD were reviewed for study completion time, liver stiffness values (LS), attenuation imaging, and shear wave dispersion slope. The ROI was placed 2 cm below the liver capsule. The study included patients with NAFLD/NASH (68), hepatitis C (30), prior Fontan surgery (1), elevated liver function tests (5), alcohol abuse (3), hepatitis B (2), and primary biliary cirrhosis (1). IQR/M values were obtained. Comparison of less experienced sonographers (LES) and more experienced sonographers (MES) were evaluated through Student’s t test for independent data. Pearson coefficient r of correlation among quantitative variables was calculated.
Aitharaju V; De Silvestri A; Barr RG
Abdominal Radiology
2021
2021-07-25
Journal Article
<table width="91" style="border-collapse:collapse;width:336px;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1007/s00261-021-03225-2">http://doi.org/10.1007/s00261-021-03225-2</a></td>
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Assessment of chronic liver disease by multiparametric ultrasound: results from a private practice outpatient facility.
ELASTOGRAPHY; NAFLD; Shear wave elastography; Liver stiffness; NASH; MANAGEMENT; Attenuation coefficient; Shear wave dispersion; FIBROSIS; GUIDELINES; HEPATIC STEATOSIS; RADIATION FORCE IMPULSE; RADIOLOGISTS; SOCIETY; STIFFNESS
PURPOSE: To assess chronic liver disease (CLD) using multiparametric US in a private practice setting in a cohort of patients with increased skin-to-liver distance. METHODS: 110 consecutive patients with increased skin-to-liver distance scheduled for US assessment of CLD were reviewed for study completion time, liver stiffness values (LS), attenuation imaging, and shear wave dispersion slope. The ROI was placed 2 cm below the liver capsule. The study included patients with NAFLD/NASH (68), hepatitis C (30), prior Fontan surgery (1), elevated liver function tests (5), alcohol abuse (3), hepatitis B (2), and primary biliary cirrhosis (1). IQR/M values were obtained. Comparison of less experienced sonographers (LES) and more experienced sonographers (MES) were evaluated through Student's t test for independent data. Pearson coefficient r of correlation among quantitative variables was calculated. RESULTS: The mean time to perform the exam was 129.7 ± 62.1 s. There was a statistically significant difference between LES and MES. The mean IQR/M for LS was 12.3 ± 5.5% m/s. Overall, in a cohort of difficult patients, 4.5% of LS values were not reliable. Fat quantification using attenuation imaging had a mean value of 0.60 ± 0.15 dB/cm/MHz (range 0.35-0.98 cm/dB/MHz) with an IQR/M of 14.7 ± 9.2%. Less reliable measurements of steatosis were obtained in 4.5% of patients. The mean shear wave dispersion slope was 12.74 ± 4.05 (m/s)/kHz (range 7.7-27.5 (m/s)/kHz) with an IQR/M of 38.7 ± 20.2% (range 3-131%). 20.9% of patients had values suggestive of compensated advanced chronic liver disease (cACLD). CONCLUSION: Multiparametric US can provide assessment of CLD in less than 3 min in most patients and identify patients at risk for cACLD.
Aitharaju V; De Silvestri A; Barr RG
Abdominal Radiology
2021
2021-07-25
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1007/s00261-021-03225-2" target="_blank" rel="noreferrer noopener">10.1007/s00261-021-03225-2</a>
Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.
miR-34a; NAFLD; Lipogenesis; bile acids; Bile acids; lipid absorption; lipogenesis; Lipid absorption
Objectives: Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice, and patients with non-alcoholic steatohepatitis (NASH), yet the role of hepatocyte miR-34a in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.; Methods: Mice over-expressing or deficient in hepatocyte miR-34a and their control mice were fed a diet enriched in fats, cholesterol and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression or reversal of NAFLD was determined.; Results: Hepatocyte-specific expression of miR-34a aggravated HFCF diet-induced NAFLD. In contrast, germline or adult-onset loss of hepatocyte miR-34a attenuated the development and progression of NAFLD. In addition, pharmacological inhibition of miR-34a reversed HFCF diet-induced steatohepatitis. Mechanistically, hepatocyte miR-34a regulated the development and progression of NAFLD by inducing lipid absorption, lipogenesis, inflammation and apoptosis, and inhibiting fatty acid oxidation.; Conclusions: Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD. (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Xu Y; Zhu Y; Hu S; Pan X; Bawa FC; Wang HH; Wang DQ; Yin L; Zhang Y
Molecular Metabolism
2021
2021-04-27
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.molmet.2021.101244" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2021.101244</a>
Early pro-inflammatory remodeling of HDL proteome in a model of diet-induced obesity: 2H2O-metabolic labeling-based kinetic approach.
inflammation; NAFLD; proteome dynamics; dyslipidemia; insulin resistance; diet-induced obesity; acute-phase proteins; high-density lipoprotein; high-fat diet
Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia.
Sadana P;Lin Li;Aghayev M;Ilchenko S;Kasumov T
International Journal of Molecular Sciences
2020
2020-10-10
journalArticle
<a href="http://doi.org/10.3390/ijms21207472" target="_blank" rel="noreferrer noopener">10.3390/ijms21207472</a>
Relationships between Very Low-Density Lipoproteins-Ceramides, -Diacylglycerols, and -Triacylglycerols in Insulin-Resistant Men.
biomarkers; Ceramides; disease; humans; inflammation; kinetics; ldl; Lipids; Metabolic syndrome; NAFLD; NAFLD; obese men; secretion; sphingolipids; VLDL; VLDL
This short report describes the relationships between concentrations of ceramides (CER), diacylglycerols (DAG), triacylglycerols (TAG) in very low-density lipoproteins (VLDL) particles, and hepatic lipid accumulation. VLDL particles were isolated from male subjects (n = 12, mean +/- SD, age 42.1 +/- 5.4 years, BMI 37.4 +/- 4.1 kg/m(2) , ALT 45 +/- 21 U/L) and apolipoprotein B100 (apoB100),
Mucinski Justine M; Manrique-Acevedo Camila; Kasumov Takhar; Garrett Timothy J; Gaballah Ayman; Parks Elizabeth J
Lipids
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/lipd.12244" target="_blank" rel="noreferrer noopener">10.1002/lipd.12244</a>
Proteome Dynamics Reveals Pro-inflammatory Remodeling Of Plasma Proteome In A Mouse Model Of Nafld
antiinflammatory properties; Atherosclerosis; Biochemistry & Molecular Biology; fatty liver-disease; gene-expression; HDL; heavy water; high-density-lipoprotein; mass-spectrometry; NAFLD; oxidized phospholipids; ppar-alpha; proteome dynamics; proteomics; rapid method; shotgun; statistical-model
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Because the liver is the major source of circulatory proteins, it is not surprising that hepatic disease could lead to alterations in the plasma proteome, which are therein implicated in atherosclerosis. The current study used low-density lipoprotein receptor-deficient (LDLR-/-) mice to examine the impact of Western diet (WD)-induced NAFLD on plasma proteome homeostasis. Using a (H2O)-H-2-metabolic labeling method, we found that a WD led to a proinflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma, which was attributed to an increased production. The fractional turnover rates of short-lived proteins that are implicated in stress-response, lipid metabolism, and transport functions were significantly increased with WD (P < 0.05). Pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPAR alpha, which was confirmed based on reduced gene and protein expression of PPAR alpha in mice fed a WD. These changes were associated with similar to 4-fold increase (P < 0.0001) in the proinflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals proinflammatory remodeling of the plasma proteome relevant to liver disease. The approach used herein may provide a useful metric of in vivo liver function and better enable studies of novel therapies surrounding NAFLD and other diseases.
Li L; Bebek G; Previs S F; Smith J D; Sadygov R G; McCullough A J; Willard B; Kasumov T
Journal of Proteome Research
2016
2016-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/acs.jproteome.6b00601" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.6b00601</a>
d2ome, Software for in Vivo Protein Turnover Analysis Using Heavy Water Labeling and LC-MS, Reveals Alterations of Hepatic Proteome Dynamics in a Mouse Model of NAFLD
40S ribosomal proteins; algorithm; amino-acids; Biochemistry & Molecular Biology; dna; in vivo protein turnover; isotopomer; Mass spectrometry; metabolic labeling; NAFLD; nonlinear least-squares modeling; peak detection and integration; proliferation; protein half-life; proteome dynamics; proteostasis; quantification; rates; respiratory-chain; steatosis; UPR
Metabolic labeling with heavy water followed by LC-MS is a high throughput approach to study proteostasis in vivo. Advances in mass spectrometry and sample processing have allowed consistent detection of thousands of proteins at multiple time points. However, freely available automated bioinformatics tools to analyze and extract protein decay rate constants are lacking. Here, we describe d2ome-a robust, automated software solution for in vivo protein turnover analysis. d2ome is highly scalable, uses innovative approaches to nonlinear fitting, implements Grubbs' outlier detection and removal, uses weighted-averaging of replicates, applies a data dependent elution time windowing, and uses mass accuracy in peak detection. Here, we discuss the application of d2ome in a comparative study of protein turnover in the livers of normal vs Western diet-fed LDLR-/- mice (mouse model of nonalcoholic fatty liver disease), which contained 256 LC-MS experiments. The study revealed reduced stability of 40S ribosomal protein subunits in the Western diet-fed mice.
Sadygov R G; Avva J; Rahman M; Lee K; Ilchenko S; Kasumov T; Borzou A
Journal of Proteome Research
2018
2018-11
Journal Article
<a href="http://doi.org/10.1021/acs.jproteorne.8b00417" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteorne.8b00417</a>
HDL Flux is Higher in Patients with Nonalcoholic Fatty Liver Disease
haevy water; HDL; NAFLD; NASH; proteomics
October 2019 Update
Altered lipid metabolism and inflammation are involved in the pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL proteins dynamics in SS (n=7), NASH patients (n=8), and healthy controls (n=9) were studied in vivo. HDL maturation and remodeling, anti-oxidant, cholesterol efflux properties, and activities of lecithin cholesterol ester acyl transferase (LCAT) and cholesterol ester transfer protein (CETP) were quantified using in vitro assays. All NAFLD patients had increased turnover of both HDL cholesterol (HDLc, 0.16±0.09 vs. 0.34±0.18 day-1, P<0.05) and ApoAI (0.26±0.04 vs. 0.34±0.06 day-1, P<0.005) compared to healthy controls. The fractional catabolic rates (FCR) of other HDL proteins, including ApoAII (and ApoAIV were higher (P<0.05) in NAFLD patients who also had higher CETP activity, ApoAI/HDLc ratio (P<0.05). NAFLD-induced alterations were associated with lower antioxidant (114.2±46.6 vs 220.5±48.2 nml/ml●min) but higher total efflux properties of HDL (23.4±1.3 vs. 25.5±2.3 %) (both P<0.05) which was more pronounced in individuals with NASH. However, no differences were observed in either HDL turnover, antioxidant and cholesterol efflux functions of HDL or HDL proteins' turnover between SS and NASH subjects. Thus, HDL metabolism and function are altered in NAFLD without any significant differences between SS and NASH.
McCullough Arthur; Previs Stephen F; Dasarathy Jaividhya; Lee Kwangwon; Osme Abdullah; Kim Chunki; Ilchenko Serguei; Lorkowski Shuhui W; Smith Jonathan D; Dasarathy Srinivasan; Kasumov Takhar
American Journal of Physiology. Endocrinology and Metabolism
2019
2019-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpendo.00193.2019" target="_blank" rel="noreferrer noopener">10.1152/ajpendo.00193.2019</a>
d2ome, Software for in Vivo Protein Turnover Analysis Using Heavy Water Labeling and LC-MS, Reveals Alterations of Hepatic Proteome Dynamics in a Mouse Model of NAFLD.
40S ribosomal proteins; in vivo protein turnover; isotopomer quantification; metabolic labeling; NAFLD; nonlinear least-squares modeling; peak detection and integration; protein half-life; proteome dynamics; UPR
Metabolic labeling with heavy water followed by LC-MS is a high throughput approach to study proteostasis in vivo. Advances in mass spectrometry and sample processing have allowed consistent detection of thousands of proteins at multiple time points. However, freely available automated bioinformatics tools to analyze and extract protein decay rate constants are lacking. Here, we describe d2ome-a robust, automated software solution for in vivo protein turnover analysis. d2ome is highly scalable, uses innovative approaches to nonlinear fitting, implements Grubbs' outlier detection and removal, uses weighted-averaging of replicates, applies a data dependent elution time windowing, and uses mass accuracy in peak detection. Here, we discuss the application of d2ome in a comparative study of protein turnover in the livers of normal vs Western diet-fed LDLR(-/-) mice (mouse model of nonalcoholic fatty liver disease), which contained 256 LC-MS experiments. The study revealed reduced stability of 40S ribosomal protein subunits in the Western diet-fed mice.
Sadygov Rovshan G; Avva Jayant; Rahman Mahbubur; Lee Kwangwon; Ilchenko Sergei; Kasumov Takhar; Borzou Ahmad
Journal of proteome research
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/acs.jproteome.8b00417" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.8b00417</a>