Alpha-Lipoic-Acid
Alpha-Lipoic Acid possesses unique redox capabilities, enabling it to exist in both reduced (dihydrolipoic acid (DHLA)) and oxidized forms. This dual nature confers potent antioxidant properties, as alpha-lipoic-acid can quench a variety of free radicals and reactive oxygen species (ROS).
Alpha-lipoic-acid serves as a vital cofactor for several mitochondrial enzyme complexes, including pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, integral for aerobic metabolism and the citric acid cycle.
Literature Review
Cholesterol Modulation: Alpha-lipoic acid taken orally appears to lower total and LDL cholesterol levels in certain groups, although its clinical effectiveness for hyperlipidemia remains unknown.
An aggregate analysis of 11 clinical trials showed that a daily dosage of alpha-lipoic acid ranging from 300-1200 mg for a period of up to 16 weeks resulted in a reduction of total cholesterol by 10 mg/dL and LDL cholesterol by 9 mg/dL. However, no impact on HDL cholesterol or triglyceride levels was observed. A separate long-term study of generally healthy adults showed that a daily dosage of 800-1200 mg for four years led to a decrease in total and LDL cholesterol as well as triglycerides.[i]
Weight Loss Effects: Most studies suggest that alpha-lipoic acid taken orally may facilitate modest weight loss. Although the results from individual clinical studies are mixed [ii],[iii],[iv],[v],[vi], meta-analyses indicate that taking 300-1800 mg of alpha-lipoic acid daily for a duration of 2-48 weeks can result in a modest weight loss of 0.7-2.3 kg and a reduction in BMI by up to 0.5 kg/m2. These changes are statistically significant but may not be clinically meaningful.[vii],[viii],[ix]
Mechanism of Action
General: Alpha-lipoic acid, when consumed through diet or supplements, has about a 30% absorption rate and gets converted to DHLA in numerous tissues.[x],[xi],[xii] It serves as a coenzyme in carbohydrate metabolism and is part of the mitochondrial citric acid cycle that produces adenosine triphosphate (ATP).[xiii],[xiv]
Anti-inflammatory effects: Alpha-lipoic acid acts as an inflammation modulator, potentially reducing vascular inflammation.[xv],[xvi] It has been found to increase levels of cyclic adenosine monophosphate (cAMP) in peripheral blood mononuclear cells in patients with multiple sclerosis when given at a 1200 mg dose. Elevated cAMP is believed to reduce inflammation and cell death.[xvii] Increasing cAMP is theorized to reduce systemic inflammation and cellular apoptosis.
A daily dose of 600 mg has been shown to decrease levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in obese patients.[xviii],[xix] Of note, negative correlations have been drawn between insulin sensitivity index and levels of TNF-alpha and IL-6 in obese patients with glucose metabolic dysregulation.67 Clinical meta-analyses suggest that 300-1200 mg of oral alpha-lipoic acid taken for 1-48 weeks can reduce IL-6 and TNF-alpha levels compared to a placebo. Some evidence also points to a decrease in C-reactive protein (CRP) levels.[xx],[xxi],[xxii],[xxiii]
Antioxidant effects: Alpha-lipoic acid and its metabolite, DHLA, exhibit antioxidant activities capable of neutralizing free radicals both within and outside cells.[xxiv] Alpha-lipoic acid is soluble in both water and fat, regenerates other antioxidants like vitamin E, vitamin C, and glutathione, and helps prevent oxidative damage.[xxv],[xxvi]
Cardiovascular effects: Alpha-lipoic acid has also been shown to reduce LDL cholesterol and may potentially lower triglycerides. It seems to inhibit platelet activity in type 1 diabetes patients, possibly reducing their cardiovascular risk.[xxvii]
Endocrine effects: Human studies show alpha-lipoic acid improving insulin levels, glucose infusion rates, and insulin sensitivity.[xxviii],[xxix],[xxx],[xxxi]. In animal models, it has restored glucose storage within nerve cells, helped prevent insulin-resistant-related vascular damage, and reduced the presence of proteins in urine due to its antioxidant properties.[xxxii],[xxxiii],[xxxiv],[xxxv]. Alpha-lipoic acid has also been observed to stimulate glucose transport, by stimulating glycolysis through the AMP-activated protein kinase pathway, and utilization, improving muscle regeneration and aiding in glucose effectiveness.[xxxvi]
In vitro, alpha-lipoic acid was found to boost the overall uptake of glucose. This was achieved by facilitating the transport of glucose via the pathway regulated by insulin.85
Alpha-lipoic acid is rich in high-energy bonds and serves as a coenzyme alongside pyrophosphate in converting pyruvic acid into acetyl-coenzyme A, a critical component of the tricarboxylic acid (TCA) cycle. Acting as a cofactor in enzyme complexes that trigger the oxidative breakdown of alpha-ketoacids, alpha-lipoic-acid lowers the concentrations of lactate and pyruvate, thereby enhancing glucose effectiveness.[xxxvii],[xxxviii]
Neurological effects: Animal studies have found alpha-lipoic-acid to reduce oxidative stress, axonal degeneration, and movement impairments by neutralizing reactive oxygen species. It has also been shown to improve nerve function and blood flow in neurons. In experimental models, alpha-lipoic-acid increases neuronal blood flow, improves neuronal glucose uptake, increases amounts of reduced glutathione in neurons, and improves neuronal conduction velocity. [xxxix]
Vascular effects: Clinical and animal research suggests alpha-lipoic-acid improves flow-mediated dilation and endothelial function. It may also mitigate the effects of TNF-alpha, potentially reducing the risk of systemic vascular inflammation development.[xl],[xli],[xlii],[xliii] Studies in animals indicate that alpha-lipoic-acid may help mitigate the decrease in endothelial nitric oxide synthase activity commonly observed with vascular issues in aging individuals.[xliv]
Additional animal studies suggest that this compound can ameliorate endothelial dysfunction in obese rats by stimulating AMP-activated protein kinase within these endothelial cells.[xlv]
Research conducted in vitro also points to alpha-lipoic-acid's ability to both downregulate proteins that are overexpressed and upregulate certain proteins that are underexpressed due to the influence of tumor necrosis factor (TNF)-alpha in vascular smooth muscle cells.[xlvi]
Given that TNF-alpha is thought to play a role in initiating and advancing vascular lesions, the modulation of its effects by alpha-lipoic-acid could potentially slow down the onset and progression of various complications of systemic vascular inflammation.
Weight loss effects: Clinical studies indicate that alpha-lipoic acid reduces leptin levels and increases adiponectin levels in patients with excessive body fat, which may play a role in preventing chronic diseases including diabetes, cardiovascular disease, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD).
Alpha-lipoic acid has also been observed to increase overall energy expenditure, likely by inhibiting hypothalamic AMP-activated protein kinase.[xlvii]
References
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