Dietary fats are important for human health, yet it is not fully understood how different fats affect various health problems. Although polyunsaturated fatty acids (PUFAs) are generally considered as ...highly oxidizable, those of the n-3 series can ameliorate the risk of many age-related disorders. Coenzyme Q (CoQ) is both an essential component of the mitochondrial electron transport chain and the only lipid-soluble antioxidant that animal cells can synthesize. Previous work has documented the protective antioxidant properties of CoQ against the autoxidation products of PUFAs. Here, we have explored in vitro and in vivo models to better understand the regulation of CoQ biosynthesis by dietary fats. In mouse liver, PUFAs increased CoQ content, and PUFAs of the n-3 series increased preferentially CoQ10. This response was recapitulated in hepatic cells cultured in the presence of lipid emulsions, where we additionally demonstrated a role for n-3 PUFAs as regulators of CoQ biosynthesis via the upregulation of several COQ proteins and farnesyl pyrophosphate levels. In both models, n-3 PUFAs altered the mitochondrial network without changing the overall mitochondrial mass. Furthermore, in cellular systems, n-3 PUFAs favored the synthesis of CoQ10 over CoQ9, thus altering the ratio between CoQ isoforms through a mechanism that involved downregulation of farnesyl diphosphate synthase activity. This effect was recapitulated by both siRNA silencing and by pharmacological inhibition of farnesyl diphosphate synthase with zoledronic acid. We highlight here the ability of n-3 PUFAs to regulate CoQ biosynthesis, CoQ content, and the ratio between its isoforms, which might be relevant to better understand the health benefits associated with this type of fat. Additionally, we identify for the first time zoledronic acid as a drug that inhibits CoQ biosynthesis, which must be also considered with respect to its biological effects on patients.
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•Dietary fats exert differential actions on CoQ biosynthesis.•n-3 PUFAs increase CoQ biosynthesis and elevate hepatic CoQ content.•CoQ biosynthesis is influenced by COQ proteins expression and FPP content.•Farnesyldiphosphate synthase plays a key role in regulating the CoQ9/CoQ10 ratio.•Zoledronic acid is identified as a drug that inhibits CoQ biosynthesis.
We analyzed NAD
metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD
boosting.
...Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD
levels and NAD
-related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti-tumor necrosis factor (anti-TNF) drugs, we evaluated changes in NAD
levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD
boosters, such as nicotinamide and nicotinamide riboside.
Reduced NAD
levels were found in RA samples, in line with altered activity and expression of genes involved in NAD
consumption (sirtuins, polyADP-ribose polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD
levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD
levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD
levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status.
RA patients display altered NAD
metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD
boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.
To examine the psychometric properties of a Spanish version of the C-SSRS (Sp-CSSRS).
Data are from a naturalistic, cross-sectional, multicentre, validation study, including 467 psychiatric ...outpatients, 242 of whom had a history of suicide attempt. The study measures were: C-SSRS; the Hamilton Depression Rating Scale (HDRS); the Beck Suicide Intent Scale; the Medical Damage Scale.
Construct validity: Pearson coefficient between the C-SSRS severity (C-Sev) and intensity (C-Int) of ideation subscale scores was 0.44 (P<.000) for the total sample. Likewise, Pearson coefficient between C-Sev score and HDRS item 3 was 0.56 (P<.000). For the sub-sample of patients with suicide attempt, significant Pearson correlations were found between the C-Sev and the Beck Suicide Intent Scale scores (r=0.22; P=.001). Discriminant validity: Significant differences were found in C-Sev and C-Int scores between patients with and without suicide attempt (P<.000). The C-Sev score discriminated between patients based on HDRS item 3 (P<.009). Sensitivity to change: Linear regression showed that a one-unit decrease in HDRS item 3 corresponded to a decrease of 5.08 units in the C-Sev score (P=.141). A one-unit change in HDRS item 3 corresponded to a change of 13.51 on the C-Int assessments (P=.007). Cronbach's alpha was 0.53 for C-Int. The principal component analysis identified 2 components that explain 55.66% of the total variance (C-Int).
The data support that the Sp-C-SSRS is a reliable and valid instrument for assessing suicidal ideation and behaviour in daily clinical practice and research settings.
Imbalance between proliferation and cell death accounts for several age-linked diseases. Aging, calorie restriction (CR), and fat source are all factors that may influence apoptotic signaling in ...liver, an organ that plays a central metabolic role in the organism. Here, we have studied the combined effect of these factors on a number of apoptosis regulators and effectors. For this purpose, animals were fed diets containing different fat sources (lard, soybean oil, or fish oil) under CR for 6 or 18 months. An age-linked increase in the mitochondrial apoptotic pathway was detected with CR, including a decrease in Bcl-2/Bax ratio, an enhanced release of cytochrome c to the cytosol and higher caspase-9 activity. However, these changes were not fully transmitted to the effectors apoptosis-inducing factor and caspase-3. CR (which abated aging-related inflammatory responses) and dietary fat altered the activities of caspases-8, -9, and -3. Apoptotic index (DNA fragmentation) and mean nuclear area were increased in aged animals with the exception of calorie-restricted mice fed a lard-based fat source. These results suggest possible protective changes in hepatic homeostasis with aging in the calorie-restricted lard group.
Biological membranes adapt their phospholipid composition according to the major lipid source present in the diet. Different dietary sources may modify the lipid pattern and produce biochemical ...alterations in cells, especially in mitochondrial membranes. For example, sources of polyunsaturated fatty acids, such as soybean or fish oil, will generate membranes more susceptible to oxidative stress than will sources of saturated or monounsaturated fatty acids, such as animal fat or olive oil, respectively. Previous studies revealed that different dietary fats also influenced the mitochondrial levels of coenzyme Q (Q), a lipid present in all organisms. Apart from participating as an electron and proton carrier in the mitochondrial electron transport chain, Q serves numerous cellular functions including metabolism, antioxidant protection, and the regulation of signal transduction. We used a hepatocellular model of Hepa1‐6 cells treated with different lipid emulsions, and focused on the regulation of Q biosynthesis and the ultrastructure of the mitochondria. Our results indicate that treatment with unsaturated fatty acids increased Q levels, which corresponded to an increase in Q biosynthetic rate in the case of polyunsaturated fatty acids (PUFA) but not in the case of monounsaturated fatty acids (MUFA). Moreover, our results indicate that PUFA regulate the different Q isoforms, and promote the biosynthesis of Q10 over Q9 thus decreasing Q9/Q10 ratio. Since most of the cellular Q is located in mitochondria, the structure, number, size and distribution of this organelle greatly influences the overall content of Q in cells. We studied the ultrastructure and the abundance of mitochondria in order to evaluate whether the regulation of Q levels by fatty acids involved an alteration of mitochondrial ultrastructure and/or mitochondrial abundance. Electron microscopy micrographs of cells showed that cells treated with n‐3 PUFA showed significantly increased mitochondrial volume and the number of mitochondria per cell, explaining in part the increase of Q levels previously described. However, these alterations in the mitochondrial ultrastructure do not explain the alteration of the Q9/Q10 ratio. Further experiments focused on the mevalonate pathway showed that the alteration of the Q9/Q10 ratio can be explained by PUFA‐mediated inhibition of farnesyl diphosphate synthase, a key enzyme in this pathway. However, the observed increase of Q biosynthesis may implicate additional target(s). Immunostaining analyses reveal that PUFA exert an stimulatory effect on some of the COQ proteins involved in Q biosynthesis pathway. Further studies will be needed to fully understand the exact regulation that fatty acids exert on Q metabolism and mitochondrial ultrastructure.
Support or Funding Information
BFU2015‐64630‐R and BFU2011‐23578 Projects from the Spanish Ministery of Economy. 1R01AG028125‐01A1 Project from NIH. FPU12/03398 Scholarship from the Spanish Ministery of Education, Culture and Sport.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many ...model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H
+
leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging.
Calorie restriction decreases skeletal muscle apoptosis, and this phenomenon has been mechanistically linked to its protective action against sarcopenia of aging. Alterations in lipid composition of ...membranes have been related with the beneficial effects of calorie restriction. However, no study has been designed to date to elucidate if different dietary fat sources with calorie restriction modify apoptotic signaling in skeletal muscle. We show that a 6-month calorie restriction decreased the activity of the plasma membrane neutral sphingomyelinase, although caspase-8/10 activity was not altered, in young adult mice. Lipid hydroperoxides, Bax levels, and cytochrome
c
and AIF release/accumulation into the cytosol were also decreased, although caspase-9 activity was unchanged. No alterations in caspase-3 and apoptotic index (DNA fragmentation) were observed, but calorie restriction improved structural features of gastrocnemius fibers by increasing cross-sectional area and decreasing circularity of fibers in cross sections. Changing dietary fat with calorie restriction produced substantial alterations of apoptotic signaling. Fish oil augmented the protective effect of calorie restriction decreasing plasma membrane neutral sphingomyelinase, Bax levels, caspase-8/10, and −9 activities, while increasing levels of the antioxidant coenzyme Q at the plasma membrane, and potentiating the increase of cross-sectional area and the decrease of fiber circularity in cross sections. Many of these changes were not found when we used lard. Our data support that dietary fish oil with calorie restriction produces a cellular anti-apoptotic environment in skeletal muscle with a downregulation of components involved in the initial stages of apoptosis engagement, both at the plasma membrane and the mitochondria.
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