A Randomized Controlled Trial of Long-Term (R)-α-Lipoic Acid Supplementation Promotes Weight Loss in Overweight or Obese Adults without Altering Baseline Elevated Plasma Triglyceride Concentrations.

BACKGROUND: α-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking. OBJECTIVES: The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation. METHODS: Overweight adults [n = 81; 57% women; 21-60 y old; BMI (in kg/m2) ≥ 25] with elevated plasma triglycerides ≥100 mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-α-lipoic acid (R-LA; 600 mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints. RESULTS: R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (-0.8; P = 0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P = 0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI ≥ 35) showed greater weight loss (-5.0% and -4.8%, respectively; both P < 0.001) and loss of body fat (-9.4% and -8.6%, respectively; both P < 0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1] : +22%; P = 0.02) than in placebo. Less urinary F2-isoprostanes (-25%; P = 0.005), blood leukocytes (-10.1%; P = 0.01), blood thrombocytes (-5.1%; P = 0.03), and ICAM-1 (-7.4%; P = 0.04) at 24 wk were also observed in the R-LA group than in placebo. CONCLUSIONS: Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.This trial was registered at clinicaltrials.gov as NCT00765310.

What modulates animal longevity? Fast and slow aging in bivalves as a model for the study of lifespan.

Delineating the physiological and biochemical causes of aging process in the animal kingdom is a highly active area of research not only because of potential benefits for human health but also because aging process is related to life history strategies (growth and reproduction) and to responses of organisms to environmental conditions and stress. In this synthesis, we advocate studying bivalve species as models for revealing the determinants of species divergences in maximal longevity. This taxonomic group includes the longest living metazoan on earth (Arctica islandica), which insures the widest range of maximum life span when shorter living species are also included in the comparative model. This model can also be useful for uncovering factors modulating the pace of aging in given species by taking advantages of the wide disparity of lifespan among different populations of the same species. For example, maximal lifespan in different populations of A islandica range from approximately 36 years to over 500 years. In the last 15 years, research has revealed that either regulation or tolerance to oxidative stress is tightly correlated to longevity in this group which support further investigations on this taxon to unveil putative mechanistic links between Reactive Oxygen Species and aging process.

Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production?

Mitochondrial decay plays a central role in the aging process. Although certainly multifactorial in nature, defective operation of the electron transport chain (ETC) constitutes a key mechanism involved in the age-associated loss of mitochondrial energy metabolism. Primarily, mitochondrial dysfunction affects the aging animal by limiting bioenergetic reserve capacity and/or increasing oxidative stress via enhanced electron leakage from the ETC. Even though the important aging characteristics of mitochondrial decay are known, the molecular events underlying inefficient electron flux that ultimately leads to higher superoxide appearance and impaired respiration are not completely understood. This review focuses on the potential role(s) that age-associated destabilization of the macromolecular organization of the ETC (i.e. supercomplexes) may be important for development of the mitochondrial aging phenotype, particularly in post-mitotic tissues.

Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age.

It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) ß without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.

Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function.

New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk.

Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response.

Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24h following treatment with the dithiol micronutrient (R)-α-lipoic acid (LA; 50µM), or vehicle. LA caused a ≥2.5-fold increase in nuclear Nrf2 within 1h. However, pretreating cells with cycloheximide (50µg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P<0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli.

Biomechanical demands of exercises commonly performed by older adults in falls prevention programs.

BACKGROUND: Tailored, challenging and progressed exercise programs addressing risk factors are recommended for preventing falls in community-dwelling older adults. Knowing the biomechanical demands of exercises commonly performed in efficacious falls prevention programs provides evidence for exercise prescription. METHODS: Twenty-one non-sedentary older adults (10 men, 11 women, mean age 69 [SD 5] years) performed five standing exercises (hip abduction, side-step, squat, forward lunge, and side lunge). A biomechanical analysis of the dominant limb was performed to calculate peak joint angles and net joint moments at the ankle, knee and hip in multiple planes. Repeated-measures one-way analyses of variance followed by post-hoc comparisons were performed to identify differences in the calculated variables between exercises. FINDINGS: Peak hip abduction moments during hip abduction were greater than during the forward lunge and squat (P < 0.001). During the side-step, peak plantar flexion moments were greater than the squat and peak hip abduction moments were greater than the squat and forward lunge (P < 0.001). During the squat, peak hip flexion was greatest (P < 0.001) while peak plantar flexion (P < 0.001) and hip abduction moments (P ≤ 0.002) were less than all other exercises. During the forward lunge, peak hip extension moments (P < 0.001) were greatest. During the side lunge, peak knee extension moments were greater than all other exercises (P < 0.001). INTERPRETATION: These biomechanical data will allow clinicians to tailor exercises for falls prevention to efficiently challenge but not overload muscle groups and minimize exercise prescription redundancies.

Multivitamin/Multimineral Supplementation Prevents or Reverses Decline in Vitamin Biomarkers and Cellular Energy Metabolism in Healthy Older Men: A Randomized, Double-Blind, Placebo-Controlled Study.

Despite the reported prevalence of micronutrient deficiencies in older adults, it is not yet established whether multivitamin/multimineral (MV/MM) supplements improve blood micronutrient status in individuals over the age of 65. Therefore, a cohort of 35 healthy men (>67 years) was recruited for an MV/MM supplementation trial. The primary endpoint was, as an indicator of micronutrient status, changes in blood micronutrient biomarkers from baseline to at least six months of supplementation with MV/MM or placebo. The secondary endpoint was basal O2 consumption in monocytes as an indicator of cellular metabolism. MV/MM supplementation improved blood concentrations of pyridoxal phosphate, calcifediol, α-tocopherol, and ß-carotene concentrations throughout the cohort. By contrast, those in the placebo group generally showed declines in blood vitamin concentrations and an increased prevalence of suboptimal vitamin status during the study period. On the other hand, MV/MM supplementation did not significantly affect blood mineral concentrations, i.e., calcium, copper, iron, magnesium, and zinc. Interestingly, MV/MM supplementation prevented the decline in monocyte O2 consumption rate. Overall, MV/MM use improves or prevents declines in vitamin, but not mineral, status and limits declines in cellular O2 consumption, which may have important implications for metabolism and immune health in healthy older men.

R-α-lipoic acid does not reverse hepatic inflammation of aging, but lowers lipid anabolism, while accentuating circadian rhythm transcript profiles.

To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 mo) and old (24 mo) male Fischer 344 rats a diet with or without 0.2% (wt/wt) R-α-lipoic acid (LA) for 2 wk. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profiles. Results showed elevated proinflammatory gene expression in the aging liver and evidence for increased immune cell activation and tissue remodeling, together representing 45% of the age-related transcriptome changes. In addition, age-related increases in transcripts of genes related to fatty acid, triglyceride, and cholesterol synthesis, including acetyl-CoA carboxylase-ß (Acacb) and fatty acid synthase (Fasn), were observed. Supplementation of old animals with LA did not reverse the necroinflammatory phenotype but, intriguingly, altered the expression of genes governing circadian rhythm. Most notably, Arntl, Npas2, and Per changed in a coordinated manner with respect to rhythmic transcription. LA further caused a decrease in transcripts of several bile acid and lipid synthesis genes, including Acacb and Fasn, which are regulated by first-order clock transcription factors. Similar effects of LA supplementation on bile acid and lipid synthesis genes were observed in young animals. Transcript changes of lipid metabolism genes were corroborated by a decrease in FASN and ACC protein levels. We conclude that advanced age is associated with a necroinflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with lipid and energy metabolism and circadian rhythm, regardless of age.

Age and gender dependent bioavailability of R- and R,S-α-lipoic acid: a pilot study.

Lipoic acid (LA) shows promise as a beneficial micronutrient toward improving elder health. Studies using old rats show that (R)-α-LA (R-LA) significantly increases low molecular weight antioxidants that otherwise decline with age. Despite this rationale for benefiting human health, little is known about age-associated alterations in absorption characteristics of LA, or whether the commercially available racemic mixture of LA (R,S-LA) is equally as bioavailable as the naturally occurring R-enantiomer. To address these discrepancies, a pilot study was performed to establish which form of LA is most effectively absorbed in older subjects relative to young volunteers. Young adults (average age=32 years) and older adults (average age=79 years) each received 500 mg of either R- or R,S-LA. Blood samples were collected for 3h after supplementation. After a washout period they were given the other chiral form of LA not originally ingested. Results showed that 2 out of 6 elder males exhibited greater maximal plasma LA and area under the curve for the R-form of LA versus the racemic mixture. The elder subjects also demonstrated a reduced time to reach maximal plasma LA concentration following R-LA supplementation than for the racemic mixture. In contrast, young males had a tendency for increased bioavailability of R,S-LA. Overall, bioavailability for either LA isoform was much more variable between older subjects compared to young adults. Plasma glutathione levels were not altered during the sampling period. Thus subject age, and potential for varied response, should be considered when determining an LA supplementation regimen.

Supercomplex Organization of the Electron Transfer System in Marine Bivalves, a Model of Extreme Longevity.

The mitochondrial oxidative stress theory of aging suggests that the organelle's decay contributes to the aging phenotype via exacerbated oxidative stress, loss of organ coordination and energetics, cellular integrity, and activity of the mitochondrial electron transfer system (ETS). Recent advances in understanding the structure of the ETS show that the enzymatic complexes responsible for oxidative phosphorylation are arranged in supramolecular structures called supercomplexes that lose organization during aging. Their exact role and universality among organisms are still under debate. Here, we take advantage of marine bivalves as an aging model to compare the structure of the ETS among species ranging from 28 to 507 years in maximal life span. Our results show that regardless of life span, the bivalve ETS is arrayed as a set of supercomplexes. However, bivalve species display varying degrees of ETS supramolecular organization with the highest supercomplex structures found in Arctica islandica, the longest-lived of the bivalve species under study. We discuss this comparative model in light of differences in the nature and stoichiometry of these complexes and highlight the potential link between the complexity of these superstructures and longer life spans.

Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?

Mitochondria serve vital roles critical for overall cellular function outside of energy transduction. Thus, mitochondrial decay is postulated to be a key factor in aging and in age-related diseases. Mitochondria may be targets of their own decay through oxidative damage. However, treating animals with antioxidants has been met with only limited success in rejuvenating mitochondrial function or in increasing lifespan. A host of nutritional strategies outside of using traditional antioxidants have been devised to promote mitochondrial function. Dietary compounds are under study that induce gene expression, enhance mitochondrial biogenesis, mitophagy, or replenish key metabolites that decline with age. Moreover, redox-active compounds may now be targeted to mitochondria which improve their effectiveness. Herein we review the evidence that representative dietary effectors modulate mitochondrial function by stimulating their renewal or reversing the age-related loss of key metabolites. While in vitro evidence continues to accumulate that many of these compounds benefit mitochondrial function and/or prevent their decay, the results using animal models and, in some instances human clinical trials, are more mixed and sometimes even contraindicated. Thus, further research on optimal dosage and age of intervention are warranted before recommending potential mitochondrial rejuvenating compounds for human use.

Antioxidants to enhance fertility: role of eNOS and potential benefits.

The use of antioxidants is now often used as a pharmacological adjunct to limit infertility. Indeed, the lay public rightly perceives oxidative stress and, thus, antioxidant treatment as important modulators of infertility. While the direct effects of antioxidant treatment on the quality of semen and oocytes are still under investigation, a significant body of evidence points to loss of vascular tone as a root-cause of erectile dysfunction and, possibly, alterations to female reproduction. In this article, we will critically review the often neglected link between vascular dysfunction and infertility. A particular emphasis will be on the potential use of antioxidants to increase fertility and promote conception.

(R)-α-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria.

Inflammation results in heightened mitochondrial ceramide levels, which cause electron transport chain dysfunction, elevates reactive oxygen species, and increases apoptosis. As mitochondria in aged hearts also display many of these characteristics, we hypothesized that mitochondrial decay stems partly from an age-related ceramidosis that heretofore has not been recognized for the heart. Intact mitochondria or their purified inner membranes (IMM) were isolated from young (4-6 mo) and old (26-28 mo) rats and analyzed for ceramides by LC-MS/MS. Results showed that ceramide levels increased by 32% with age and three ceramide isoforms, found primarily in the IMM (e.g. C(16)-, C(18)-, and C(24:1)-ceramide), caused this increase. The ceramidosis may stem from enhanced hydrolysis of sphingomyelin, as neutral sphingomyelinase (nSMase) activity doubled with age but with no attendant change in ceramidase activity. Because (R)-α-lipoic acid (LA) improves many parameters of cardiac mitochondrial decay in aging and lowers ceramide levels in vascular endothelial cells, we hypothesized that LA may limit cardiac ceramidosis and thereby improve mitochondrial function. Feeding LA [0.2%, w/w] to old rats for two weeks prior to mitochondrial isolation reversed the age-associated decline in glutathione levels and concomitantly improved Complex IV activity. This improvement was associated with lower nSMase activity and a remediation in mitochondrial ceramide levels. In summary, LA treatment lowers ceramide levels to that seen in young rat heart mitochondria and restores Complex IV activity which otherwise declines with age.

Divergences in the Control of Mitochondrial Respiration Are Associated With Life-Span Variation in Marine Bivalves.

The role played by mitochondrial function in the aging process has been a subject of intense debate in the past few decades, as part of the efforts to understand the mechanistic basis of longevity. The mitochondrial oxidative stress theory of aging suggests that a progressive decay of this organelle's function leads to an exacerbation of oxidative stress, with a deleterious impact on mitochondrial structure and DNA, ultimately promoting aging. Among the traits suspected to be associated with longevity is the variation in the regulation of oxidative phosphorylation, potentially affecting the management of oxidative stress. Longitudinal studies using the framework of metabolic control analysis have shown age-related differences in the flux control of respiration, but this approach has seldom been taken on a comparative scale. Using 4 species of marine bivalves exhibiting a large range of maximum life span (from 28 years to 507 years), we report life-span-related differences in flux control at different steps of the electron transfer system. Increased longevity was characterized by a lower control by NADH (complex I-linked) and Succinate (complex II-linked) pathways, while respiration was strongly controlled by complex IV when compared to shorter-lived species. Complex III exerted strong control over respiration in all species. Furthermore, high longevity was associated with higher citrate synthase activity and lower ATP synthase activity. Relieving the control exerted by the electron entry pathways could be advantageous for reaching higher longevity, leading to increased control by complex IV, the final electron acceptor in the electron transfer system.

Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential.

Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.

Characteristics of the rat cardiac sphingolipid pool in two mitochondrial subpopulations.

Mitochondrial sphingolipids play a diverse role in normal cardiac function and diseases, yet a precise quantification of cardiac mitochondrial sphingolipids has never been performed. Therefore, rat heart interfibrillary mitochondria (IFM) and subsarcolemmal mitochondria (SSM) were isolated, lipids extracted, and sphingolipids quantified by LC-tandem mass spectrometry. Results showed that sphingomyelin (approximately 10,000 pmol/mg protein) was the predominant sphingolipid regardless of mitochondrial subpopulation, and measurable amounts of ceramide (approximately 70 pmol/mg protein) sphingosine, and sphinganine were also found in IFM and SSM. Both mitochondrial populations contained similar quantities of sphingolipids except for ceramide which was much higher in SSM. Analysis of sphingolipid isoforms revealed ten different sphingomyelins and six ceramides that differed from 16- to 24-carbon units in their acyl side chains. Sub-fractionation experiments further showed that sphingolipids are a constituent part of the inner mitochondrial membrane. Furthermore, inner membrane ceramide levels were 32% lower versus whole mitochondria (45 pmol/mg protein). Three ceramide isotypes (C20-, C22-, and C24-ceramide) accounted for the lower amounts. The concentrations of the ceramides present in the inner membranes of SSM and IFM differed greatly. Overall, mitochondrial sphingolipid content reflected levels seen in cardiac tissue, but the specific ceramide distribution distinguished IFM and SSM from each other.

Hepatocyte nuclear factor 1 is essential for transcription of sodium-dependent vitamin C transporter protein 1.

Transport and distribution of vitamin C is primarily regulated by the function of sodium-dependent vitamin C transporters (SVCTs). SVCT1 is expressed in the small intestine, liver, and kidney, organs that play a vital role in whole body vitamin C homeostasis. Despite the importance of this protein, little is known about regulation of the gene encoding SVCT1, Slc23a1. In this study, we present the first investigation of the transcriptional regulation of human Slc23a1, identifying transcription factors that may influence its expression. A 1,239-bp genomic DNA fragment corresponding to the 5'-flanking region of Slc23a1 was isolated from a human hepatocarcinoma cell line (HepG2) and sequenced. When cloned into a reporter gene construct, robust transcriptional activity was seen in this sequence, nearly 25-fold above the control vector. Deletion analysis of the SVCT1 reporter gene vector defined the minimal active promoter as a small 135-bp region upstream of the transcriptional start site. While several transcription factor binding sites were identified within this sequence, reporter constructs showed that basal transcription required the binding of hepatic nuclear factor 1 (HNF-1) to its cognate sequence. Furthermore, mutation of this HNF-1 binding site resulted in complete loss of luciferase expression, even in the context of the whole promoter. Additionally, small interfering RNA knockdown of both members of the HNF-1 family, HNF-1alpha and HNF-1beta, resulted in a significant decline in SVCT1 transcription. Together, these data suggest that HNF-1alpha and/or HNF-1beta binding is required for SVCT1 expression and may be involved in the coordinate regulation of whole body vitamin C status.

Dietary alpha-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E-deficient and apolipoprotein E/low-density lipoprotein receptor-deficient mice.

BACKGROUND: Vascular inflammation and lipid deposition are prominent features of atherosclerotic lesion formation. We have shown previously that the dithiol compound alpha-lipoic acid (LA) exerts antiinflammatory effects by inhibiting tumor necrosis factor-alpha- and lipopolysaccharide-induced endothelial and monocyte activation in vitro and lipopolysaccharide-induced acute inflammatory responses in vivo. Here, we investigated whether LA inhibits atherosclerosis in apolipoprotein E-deficient (apoE-/-) and apoE/low-density lipoprotein receptor-deficient mice, 2 well-established animal models of human atherosclerosis. METHODS AND RESULTS: Four-week-old female apoE-/- mice (n=20 per group) or apoE/low-density lipoprotein receptor-deficient mice (n=21 per group) were fed for 10 weeks a Western-type chow diet containing 15% fat and 0.125% cholesterol without or with 0.2% (wt/wt) R,S-LA or a normal chow diet containing 4% fat without or with 0.2% (wt/wt) R-LA, respectively. Supplementation with LA significantly reduced atherosclerotic lesion formation in the aortic sinus of both mouse models by approximately 20% and in the aortic arch and thoracic aorta of apoE-/- and apoE/low-density lipoprotein receptor-deficient mice by approximately 55% and 40%, respectively. This strong antiatherogenic effect of LA was associated with almost 40% less body weight gain and lower serum and very low-density lipoprotein levels of triglycerides but not cholesterol. In addition, LA supplementation reduced aortic expression of adhesion molecules and proinflammatory cytokines and aortic macrophage accumulation. These antiinflammatory effects of LA were more pronounced in the aortic arch and the thoracic aorta than in the aortic sinus, reflecting the corresponding reductions in atherosclerosis. CONCLUSIONS: Our study shows that dietary LA supplementation inhibits atherosclerotic lesion formation in 2 mouse models of human atherosclerosis, an inhibition that appears to be due to the "antiobesity," antihypertriglyceridemic, and antiinflammatory effects of LA. LA may be a useful adjunct in the prevention and treatment of atherosclerotic vascular diseases.

Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.

Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week-old Zucker Diabetic Fatty (ZDF) rats were fed a diet containing (R)-alpha-lipoic acid (LA, approximately 200mg/kg body weight per day) for 5 weeks. LA offset the rise in blood and liver TG by inhibiting liver lipogenic gene expression (e.g. sn-glycerol-3-phosphate acyltransferase-1 and diacylglycerol O-acyltransferase-2), lowering hepatic TG secretion, and stimulating clearance of TG-rich lipoproteins. LA-induced TG lowering was not due to the anorectic properties of LA, as pair-fed rats developed hypertriglyceridemia. Livers from LA-treated rats exhibited elevated glycogen content, suggesting dietary carbohydrates were stored as glycogen rather than becoming lipogenic substrate. Although AMP-activated protein kinase (AMPK) reportedly mediates the metabolic effects of LA in rodents, no change in AMPK activity was observed, suggesting LA acted independently of this kinase. The hepatic expression of peroxisome proliferator activated receptor alpha (PPARalpha) target genes involved in fatty acid beta-oxidation was either unchanged or decreased with LA, indicating a different mode of action than for fibrate drugs. Given its strong safety record, LA may have potential clinical applications for the treatment or prevention of hypertriglyceridemia and diabetic dyslipidemia.