Adipose tissue metabolism is closely linked to insulin resistance, and differential fat distributions are associated with disorders like hypertension, diabetes, and cardiovascular disease. Adipose ...tissues vary in their impact on metabolic risk due to diverse gene expression profiles, leading to differences in lipolysis and in the production and release of adipokines and cytokines, thereby affecting the function of other tissues. In this paper, the roles of the various adipose tissues in obesity are summarized, with particular focus on mitochondrial function. In addition, we discuss how a functionally mitochondrial-targeted compound, the modified fatty acid tetradecylthioacetic acid (TTA), can influence mitochondrial function and decrease the size of specific fat depots.
A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic ...inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes
and
, which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 2.9-8.6 vs. 3.2 2.2-6.3,
= 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor (
= 0.008, rho = 0.26), interleukin-12 (
= 0.012, rho = 0.25) and LPS (
= 0.034, rho = 0.21). Dietary intake of meat (
= 0.678), fish (
= 0.715), egg (
= 0.138), dairy products (
= 0.284), and fiber (
= 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin (
= 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of
(
= 0.021, rho = 0.36). Bacterial gene
was present in significantly more CVID samples (75%) than controls (53%),
= 0.020, potentially related to the increased abundance of
in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of
in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID.
Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the progression of HIV infection. Plasma ...levels of 45 FAs were analyzed with gas chromatography in healthy controls and HIV-infected patients with regard to Mycobacterium avium complex (MAC) infection. In vitro, we assessed MAC-PPD-induced release of inflammatory cytokines in peripheral and bone marrow mononuclear cells (PBMC and BMMC) according to levels of n-6 polyunsaturated fatty acids (PUFAs). While plasma saturated FAs were higher in HIV infection, PUFAs, and in particular the n-6 PUFA arachidonic acid (AA), were lower in patients with advanced disease. The ratio between AA and precursor dihomo-γ-linolenic acid, reflecting Δ5-desaturase activity, was markedly lower and inversely correlated with plasma HIV RNA levels in these patients. Depletion of AA was observed prior to MAC infection, and MAC-PPD-induced release of TNF and IL-6 in PBMC and BMMC was lower in patients with low plasma AA. Our findings suggest that dysregulated metabolism of n-6 PUFAs may play a role in the progression of HIV infection. While high AA may contribute to chronic inflammation in asymptomatic HIV-infected patients, low AA seems to increase the susceptibility to MAC infection in patients with advanced disease.
The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty ...acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels.
C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (
/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (
= 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver.
The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced.
This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels.
The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such ...as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.
Purpose
Triglycerides (TG) and their major transport lipoprotein in the circulation (VLDL) appear to be related to inflammation. Patients with common variable immunodeficiency (CVID) have ...inflammatory complications associated with gut microbial dysbiosis. We hypothesized that CVID patients have disturbed TG/VLDL profiles associated with these clinical characteristics.
Methods
We measured plasma concentrations of TGs, inflammatory markers, and lipopolysaccharide (LPS) in 95 CVID patients and 28 healthy controls. Additionally, in 40 CVID patients, we explored plasma lipoprotein profiling, fatty acid, gut microbial dysbiosis, and diet.
Results
TG levels were increased in CVID patients as compared to healthy controls (1.36 ± 0.53 mmol/l versus 1.08 ± 0.56 mean, SD, respectively,
P
= 0.008), particularly in the clinical subgroup “
Complications
,” characterized by autoimmunity and organ-specific inflammation, compared to “
Infection only
” (1.41 mmol/l, 0.71median, IQR versus 1.02 mmol/l, 0.50,
P
= 0.021). Lipoprotein profile analyses showed increased levels of all sizes of VLDL particles in CVID patients compared to controls. TG levels correlated positively with CRP (rho = 0.256,
P
= 0.015), IL-6 (rho = 0.237,
P
= 0.021), IL-12 (rho = 0.265,
P
= 0.009), LPS (
r
= 0.654,
P
= 6.59 × 10
−13
), CVID-specific gut dysbiosis index (
r
= 0.315,
P
= 0.048), and inversely with a favorable fatty acid profile (docosahexaenoic acid rho = − 0.369,
P
= 0.021 and linoleic acid rho = − 0.375,
P
= 0.019). TGs and VLDL lipids did not appear to be associated with diet and there were no differences in body mass index (BMI) between CVID patients and controls.
Conclusion
We found increased plasma levels of TGs and all sizes of VLDL particles, which were associated with systemic inflammation, LPS, and gut dysbiosis in CVID, but not diet or BMI.
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterized by inadequate antibody responses and recurrent bacterial infections. Paradoxically, a ...majority of CVID patients have non-infectious inflammatory and autoimmune complications, associated with systemic immune activation. Our aim was to explore if HDL, known to have anti-inflammatory properties, had impaired function in CVID patients and thereby contributed to their inflammatory phenotype. We found reduced HDL cholesterol levels in plasma of CVID patients compared to healthy controls, particularly in patients with inflammatory and autoimmune complications, correlating negatively with inflammatory markers CRP and sCD25. Reverse cholesterol transport capacity testing showed reduced serum acceptance capacity for cholesterol in CVID patients with inflammatory and autoimmune complications. They also had reduced cholesterol efflux capacity from macrophages to serum and decreased expression of ATP-binding cassette transporter ABCA1. Human HDL suppressed TLR2-induced TNF release less in blood mononuclear cells from CVID patients, associated with decreased expression of transcriptional factor ATF3. Our data suggest a link between impaired HDL function and systemic inflammation in CVID patients, particularly in those with autoimmune and inflammatory complications. This identifies HDL as a novel therapeutic target in CVID as well as other more common conditions characterized by sterile inflammation or autoimmunity.
Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the β-position. This modification renders TTA unable to undergo complete β-oxidation and increases its ...biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.
Background
Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known ...whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris.
Methods and Results
This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow‐up, 10.0% of the patients died of cardiovascular disease and 12.8% suffered a fatal or nonfatal acute myocardial infarction. Higher levels of the even‐chained acetyl‐, octanoyl‐, and palmitoyl‐carnitines were significantly associated with elevated risk of cardiovascular death, also after multivariable adjustments (HR 95% CI: 1.52 1.12, 2.06; P=0.007; 1.73 1.23, 2.44; P=0.002; and 1.61 1.18, 2.21; P=0.003, respectively), whereas their associations with acute myocardial infarction were less consistent.
Conclusions
Among patients with suspected stable angina pectoris, elevated serum even‐chained acylcarnitines were associated with increased risk of cardiovascular death and, to a lesser degree with acute myocardial infarction, independent of traditional risk factors.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354081.
Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact ...underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.
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