Severe Disease Activity and Liver Fibrosis Are Associated With a Lack of Hepatic Mitochondrial Adaptation in Patients With NASH

Abstract Dysfunctional mitochondrial function is believed to play a vital role in the progression of nonalcoholic steatohepatitis (NASH) to advanced fibrosis and cirrhosis. However, most evidence arises from animal models while there is limited data in humans. The characteristic histological finding of NASH is hepatocellular injury with ballooning and inflammation, often associated with fibrosis in advanced disease. The aim of this study was to assess the role of mitochondrial function (eg, oxidative phosphorylation [OXPHOS] in patients with vs. without NASH and fibrosis. To this end, we recruited 38 patients with NAFLD with risk factors (obesity and/or type 2 diabetes) for NASH (age: 52±12 years; 37% male; BMI: 39.6±8.5 kg/m2; HbA1c: 6.8±1.4%) in whom we assessed mitochondrial respiration and also performed measurements of insulin resistance (IR). Tissue was obtained by either a Tru-cut percutaneous liver biopsy (n=26) or a wedge biopsy during bariatric surgery (n=12). After tissue was separated for histological diagnosis, small liver samples (2–4 mg) were processed to quantify OXPHOS by measuring the mitochondrial oxygen consumption rate in individual complexes of mitochondria, expressed as pmol×mg wet weight-1×s-1, using high-resolution respirometry, Oxygraph-2k. Based on liver histology, patients with NASH (n=18) compared to without NASH (n=20), had worse hyperinsulinemia and HOMA-IR (25.2±10.5 vs 14.9± 6.7 µU/ml and 8.9±4.3 vs. 4.9±2.9 mg/dl × µU/ml, respectively) and higher OXPHOS (all p<0.05), although well matched for age, BMI, HbA1c and % with diabetes. This was likely an adaptation to IR and higher FFA flux to the liver. We then examined patients based specifically on disease activity, using a combined score of hepatocyte ballooning and inflammation (necroinflammation score [NIS]) and divided as mild (n=16), moderate (n=14) or severe (n=8) NIS (also well matched for relevant clinical parameters). Patients in the moderate vs. mild NIS group disease activity had increased mitochondrial respiration as represented by OXPHOS (45.9±11.8 vs. 31.3±9.8), electron transport chain activity (ETC) (61.0±17.6 vs. 46.4±15.2) and state 3 respiration induced by ADP (20.7±4.9 vs. 16.4±4.6 pmol×mg wet weight-1×s-1; all p<0.05). There was a trend for these parameters to decline in patients with severe vs. moderate disease activity, that was further accentuated when patients with NASH also had clinically significant fibrosis compared to those with mild or no fibrosis (OXPHOS: 37.9±7.8 vs. 49.8±12.5, p=0.04; and ETC: 49.8±13.4 vs. 67.5±16.1, p=0.02). Conclusion: In patients with NASH, there is an early hepatic mitochondrial adaptation to account for the state of more severe insulin resistance in steatohepatitis compared to simple steatosis. This adaptation is impaired when disease activity worsens and is most evident once patients develop steatohepatitis with significant fibrosis.

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A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00084.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. E503-E512 ◽

Cited By ~ 2

Author(s):

Shannon Rose ◽

Eugenia Carvalho ◽

Eva C. Diaz ◽

Matthew Cotter ◽

Sirish C. Bennuri ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Blood Cells ◽

Muscle Fibers ◽

Circulating Cells ◽

Permeabilized Muscle

Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets, and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25–35 yr) women of varying body mass indexes. With the use of extracellular flux analysis and high-resolution respirometry, mitochondrial respiration was measured in intact blood cells as well as in permeabilized cells and permeabilized muscle fibers. Respiratory parameters were not correlated between permeabilized muscle fibers and intact PBMCs or platelets. In a subset of samples ( n = 12–13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman’s ρ = 0.64, P = 0.030; Spearman’s ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.

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1891-P: Palmitate-Enriched Lipid Ingestion Acutely Induces Insulin Resistance Associated with PKCγ Activation and Impaired Mitochondrial Function in Human Skeletal Muscle

Diabetes ◽

10.2337/db20-1891-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1891-P

Author(s):

THERESIA SARABHAI ◽

CHRYSI KOLIAKI ◽

SABINE KAHL ◽

DOMINIK PESTA ◽

LUCIA MASTROTOTARO ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Function ◽

Human Skeletal Muscle

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SAT0111 THE RELATIONSHIP BETWEEN THE ADMINISTRATION OF IL-6 INHIBITORS AND INSULIN RESISTANCE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6509 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 989.3-989

Author(s):

A. Jitaru ◽

C. Pomirleanu ◽

M. M. Leon-Constantin ◽

F. Mitu ◽

C. Ancuta

Keyword(s):

Rheumatoid Arthritis ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Beneficial Effect ◽

Disease Activity ◽

Interleukin 6 ◽

Normal Weight ◽

Diabetic Patients ◽

Model Assessment ◽

Inflammatory Status

Background:Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, due not only to the traditional risk factors (hypertension, insulin resistance/diabetes, obesity, smoking), but to the inflammatory status as well. The blockade of interleukin-6 (IL-6) can regulate the glucose metabolism, reducing the glucose level and insulin resistance (IR). This beneficial effect is seen more in patients with normal values of body mass index (BMI), compared to the obese population.Objectives:Given the mentioned existing data, we aim to demonstrate the positive effect of IL-6 inhibitors in active RA patients with normal or increased BMI.Methods:We recruited 56 consecutive patients with definite and active RA, non-responders/partial responders to conventional synthetic Drug Modifying Anti-Rheumatic Drugs (csDMARDs)/biological therapy. For a period of 52 weeks, patients received subcutaneous Tocilizumab (TCZ) in a dose of 162mg once a week, according to European League Anti Rheumatism (EULAR) recommendation and National Protocol. We assessed demographics, RA-related parameters (clinical, inflammatory and immune) and metabolic markers, as well as the peripheral response to insulin, quantified by Homeostasis Model Assessment for insulin resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI). We did not include in the study the patients known with diabetes mellitus (DM) and those undergoing glucocorticoids.Results:After 52 weeks of treatment, most of the patients showed a statistically significant reduction of HOMA-IR (3.61 ± 1.21 at the onset vs. 2.45 ± 1.46 at the end of the study, p<0.001), while QUICKI registered a slight increase (0.32 ± 0.01 at the onset vs. 0.33 ± 0.01 at the end of the study, p<0.001). Also, the decrease in insulin and glucose levels were more obvious in patients with normal BMI, strictly related to disease activity.Conclusion:Long-term administration of TCZ in active RA is associated with a significant reduction of disease activity and IR, especially in normal weight patients. This confirms that obesity, as a CV risk factor, represents one of the main causes of IR.References:[1]Castañeda S, Remuzgo-Martínez S, López-Mejías R et al. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis.Clin Exp Rheumatol. 2019; 37(3):465-473.[2]Lehrskov LL, Christensen RH. The role of interleukin-6 in glucose homeostasis and lipid metabolism.Semin Immunopathol. 2019; 41(4):491-499.[3]Ursini F, Russo E, Ruscitti P, Giacomelli R, De Sarro G. The effect of non-TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis.Autoimmun Rev. 2018 Apr;17(4):399-404.Disclosure of Interests:Alexandra Jitaru: None declared, Cristina Pomirleanu: None declared, Maria-Magdalena Leon-Constantin: None declared, Florin Mitu: None declared, CODRINA ANCUTA Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly, Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly

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When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22094617 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4617

Author(s):

Styliana Kyriakoudi ◽

Anthi Drousiotou ◽

Petros P. Petrou

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Human Disease ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Mitochondrial Morphology ◽

Disease Development ◽

Pathological Conditions ◽

Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

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Galectin-9 expression correlates with therapeutic effect in rheumatoid arthritis

Scientific Reports ◽

10.1038/s41598-021-85152-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jiao Sun ◽

Yameng Sui ◽

Yunqing Wang ◽

Lijun Song ◽

Dong Li ◽

...

Keyword(s):

T Cell ◽

Disease Activity ◽

Therapeutic Effect ◽

Mean Fluorescence Intensity ◽

Therapeutic Response ◽

Severe Disease ◽

T Cell Subsets ◽

Poor Responders ◽

Lower Plasma ◽

Immunological Parameters

AbstractGalectin-9 (Gal-9) is a multifunctional immunomodulatory factor highly expressed in RA. This study aimed to investigate the expression of Gal-9 and its correlation with disease activity and therapeutic response in RA patients. Active RA patients were enrolled and treated with tacrolimus (TAC) alone or in combination therapy for 12 weeks in a prospective cohort study. Clinical and immunological parameters were recorded at baseline and week 12. We measured Gal-9 expression in different T cell subsets and in plasma. The disease activity of RA patients decreased after treatment. At baseline, the Gal-9 expression percentage was higher in the group with severe disease than in mild or moderate groups. After treatment, the Gal-9 expression in CD3+, CD4+, CD8+ and CD4-CD8− cell subsets decreased, as well as Gal-9 mean fluorescence intensity in CD3+, CD4+ and CD8+ T cells. Similarly, plasma Gal-9 levels were lower at week 12 than at baseline. Good responders showed significantly lower Gal-9 expression on CD3+ and CD4+ T cell subsets and lower plasma Gal-9 levels than poor responders. Gal-9 expression positively correlates with disease activity in RA patients. Gal-9 can be regarded as a new biomarker for evaluating RA activity and therapeutic effect, including TAC.

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Targeting Mitochondria in Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms22126642 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6642

Author(s):

Nina Krako Jakovljevic ◽

Kasja Pavlovic ◽

Aleksandra Jotic ◽

Katarina Lalic ◽

Milica Stoiljkovic ◽

...

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Whole Body ◽

Noncommunicable Diseases ◽

Pharmacological Interventions ◽

Cellular Energy ◽

Cellular Energy Metabolism ◽

Data Comparison ◽

Selection Of

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

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Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00744.2010 ◽

2011 ◽

Vol 301 (5) ◽

pp. H2093-H2101 ◽

Cited By ~ 5

Author(s):

Baptiste Kurtz ◽

Helene B. Thibault ◽

Michael J. Raher ◽

John R. Popovich ◽

Sharon Cawley ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Insulin Resistance ◽

Mitochondrial Respiration ◽

Pressure Overload ◽

Lv Remodeling ◽

Stress Levels ◽

Nitric Oxide Synthase 3 ◽

And Function ◽

Oxide Synthase

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

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Patients with Rheumatoid Arthritis in Clinical Remission Manifest Persistent Joint Inflammation on Histology and Imaging Studies

The Journal of Rheumatology ◽

10.3899/jrheum.140411 ◽

2014 ◽

Vol 41 (11) ◽

pp. 2153-2160 ◽

Cited By ~ 26

Author(s):

Allen Anandarajah ◽

Ralf Thiele ◽

Ellen Giampoli ◽

Johnny Monu ◽

Gwy-Suk Seo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Clinical Remission ◽

Severe Disease ◽

Joint Inflammation ◽

Imaging Studies ◽

American College Of Rheumatology ◽

Remission Criteria ◽

Magnetic Resonance Imaging Mri ◽

Active Inflammation

Objective.The purpose of our study was to test the hypothesis that synovitis on magnetic resonance imaging (MRI) and ultrasound (US) observed in patients with rheumatoid arthritis (RA) who meet remission criteria reflects active inflammation on histopathology.Methods.We analyzed 15 synovial specimens obtained during surgical procedures from 14 patients with RA in clinical remission as defined by the American College of Rheumatology criteria. Histological specimens were scored for hyperplasia of synovial lining and synovial stroma, inflammation, lymphoid follicles, and vascularity. The histology scores were classified as minimal, mild, moderate, or severe disease activity. US and MRI performed within a 4-month period of surgery were scored for disease activity. The correlation between histology and imaging scores was examined.Results.Four of 14 patients were receiving anti-tumor necrosis factor (TNF) therapy, 4 were receiving methotrexate (MTX) alone, 4 were taking MTX and hydroxychloroquine (HCQ), and 1 was taking HCQ and sulfasalazine. Four specimens had severe, 6 moderate, 3 mild, and 2 minimal disease activity on histology. Three of 4 specimens with minimal and mild histology were observed in subjects receiving anti-TNF therapy. Synovitis was noted on greyscale in 80% of joints and Doppler signal in 60%. MRI demonstrated synovitis and bone marrow edema in 86% of images. Positive but not significant correlations were noted between histology and synovitis scores on US.Conclusion.Despite clinical remission, histology and imaging studies documented a persistently active disease state that may explain the mechanism for radiographic progression.

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Impact of disease activity on impaired glucose metabolism in patients with rheumatoid arthritis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02476-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Gorica G. Ristić ◽

Vesna Subota ◽

Dejana Stanisavljević ◽

Danilo Vojvodić ◽

Arsen D. Ristić ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Insulin Resistance ◽

Glucose Metabolism ◽

Disease Activity ◽

Impaired Glucose Metabolism ◽

Inflammation Markers ◽

C Peptide ◽

Related Risk ◽

The Impact

Abstract Objective To explore glucose metabolism in rheumatoid arthritis (RA) and its association with insulin resistance (IR) risk factors and disease activity indicators, including matrix metalloproteinase-3 (MMP3). Methods This single-center study included 127 non-diabetic subjects: 90 RA patients and 37 matched controls. IR-related risk factors, disease activity (DAS28-ESR/CRP), concentrations of inflammation markers, MMP3, glucose, specific insulin, and C-peptide (a marker of β-cell secretion) were determined. Homeostasis Model Assessment was used to establish insulin resistance (HOMA2-IR) and sensitivity (HOMA2-%S). Associations of HOMA2 indices with IR-related risk factors, inflammation markers, and RA activity were tested using multiple regression analyses. Results RA patients had significantly increased HOMA2-IR index than controls. In the RA group, multivariate analysis revealed DAS28-ESR, DAS28-CRP, tender joint counts, patient’s global assessment, and MMP3 level as significant positive predictors for HOMA2-IR (β = 0.206, P = 0.014; β = 0.192, P = 0.009; β = 0.121, P = 0.005; β = 0.148, P = 0.007; β = 0.075, P = 0.025, respectively), and reciprocal negative for HOMA2-%S index. According to the value of the coefficient of determination (R2), DAS28-ESR ≥ 5.1 has the largest proportion of variation in both HOMA2-IR indices. DAS28-ESR ≥ 5.1 and ESR were independent predictors for increased C-peptide concentration (β = 0.090, P = 0.022; β = 0.133, P = 0.022). Despite comparability regarding all IR-related risk factors, patients with DAS28-ESR ≥ 5.1 had higher HOMA2-IR than controls [1.7 (1.2–2.5) vs. 1.2 (0.8–1.4), P = 0.000]. There was no difference between patients with DAS28-ESR < 5.1 and controls [1.3 (0.9–1.9) vs. 1.2 (0.8–1.4), P = 0.375]. Conclusions RA activity is an independent risk factor for impaired glucose metabolism. DAS28-ESR ≥ 5.1 was the main contributor to this metabolic disturbance, followed by MMP3 concentration, outweighing the impact of classic IR-related risk factors.

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Abstract 131: Anti-inflammatory and Mitochondrial Effects of Butyrate in Shr Astrocytes in vitro

Circulation Research ◽

10.1161/res.121.suppl_1.131 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Tao Yang ◽

Ty Redler ◽

Carla G Bueno Silva ◽

Rebeca Arocha ◽

Jordan Schmidt ◽

...

Keyword(s):

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Rna Isolation ◽

Inflammatory Factors ◽

Pcr Analysis ◽

Sprague Dawley ◽

Beneficial Effects ◽

Sd Rats ◽

Anti Inflammatory

Emerging evidence demonstrates a significant link between gut dysbiosis and hypertension (HTN). Butyrate is one of the major fermented end-products of gut microbiota that reportedly produces beneficial effects on the immune system and metabolism. A contraction in butyrate-producing bacteria in the gut of spontaneously hypertensive rats (SHR) suggests that reduced butyrate may be associated with HTN. Considering its role in mitochondrial metabolism, we proposed that the positive anti-inflammatory effects of butyrate may be mediated via improvement in mitochondrial function in astrocytes. Methods: Sprague Dawley (SD) and SHR primary astrocytes from two-day old pups were cultured in DMEM, supplemented with 10% FBS and 1% pen/strep, for 14 days, prior to treatment with butyrate (0-1mM) for 4 hours. Cells were then subjected to the Seahorse XFe24 Extracellular Flux Analyzer to evaluate mitochondrial function following butyrate treatment. Additional samples were collected for total RNA isolation for real time PCR analysis of inflammatory factors and transcripts related to mitochondrial function and stress. Results: Butyrate significantly increased both basal and maximal mitochondrial respiration (by 3-4 fold, P<0.001) and elevated proton leak (by 4 fold, P<0.01) in astrocytes from SD rats but not SHR. Furthermore, we observed a trend for an increase in both ATP-linked and non-mitochondrial respiration in SD astrocytes compared to SHR (by 2-3 fold, P=0.07). This was associated with a significant reduction in relative expression levels in catalase (by 50%, P<0.05) and a trend in reduction in Sod1 and Sod2 (by 25%-50%, P=0.1) in astrocytes harvested from SD rats but not the SHR. Conversely, butyrate significantly lowered expression of pro-inflammatory Ccl2 (by 33%, P<0.05) and Tlr4 (by 48%, P <0.05) in astrocytes of SHR, but not SD rats. Conclusion: Butyrate modulated mitochondrial bioenergetics in SD but not the SHR, suggesting that the mitochondria of astrocytes may be less sensitive to the effects of butyrate in HTN. In addition, butyrate reduced inflammatory mediators in the SHR, but had no effect in the SD rat astrocytes. Thus, central anti-inflammatory effects of butyrate may be mediated via a mitochondria-independent mechanism.

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