The Potential Use of Metabolic Cofactors in Treatment of NAFLD
Abstract
:1. Introduction
2. Potential Risks and Benefits of Metabolic Co-Factors
2.1. l-Carnitine
2.1.1. Dosage
- ⮚
- In patients with carnitine depletion in peripheral blood mononuclear cells, carnitine has been supplemented at a dose of 6 g/day for 2 weeks [31].
- ⮚
- Several studies have tested if carnitine supplementation promotes weight loss in obese subjects (4 g/L, 8 weeks) [32].
- ⮚
- Efficacy and effectiveness of carnitine supplementation for cancer-related fatigue has been analyzed in a systematic literature review and meta-analysis. Nine studies used a dose between 2 to 6 g per day [33].
- ⮚
- Impact of carnitine supplementation on plasma lipoprotein(a) concentrations have been analyzed in a recent systematic review and meta-analysis of human clinical trials. Studies used 2–4 g/day [34].
- ⮚
- A systematic review was conducted to determine the effects of carnitine on all-cause mortality and cardiovascular morbidities in the setting of acute myocardial infarction (meta-analysis of five controlled trials, n = 3108). There were no significant differences between the effects of daily carnitine supplementation of 2 g and 6 g on heart failure, unstable angina, or myocardial reinfarction [35].
- ⮚
- The effect of carnitine supplementation on the regression of NASH was evaluated in 74 patients with a clinical and pathologic diagnosis of NASH [36]. The study subjects were randomly allocated to the placebo or to the carnitine (2 g per day divided into two equal doses for 24 weeks) groups. At the end of the study, carnitine-treated patients showed significant improvements in AST, ALT, gamma-GT, total cholesterol, LDL-cholesterol, HDL-cholesterols, triglycerides, glucose, HOMA-IR, C-reactive protein, TNF-alpha, and histological scores. Thus, carnitine supplementation reduced inflammation, and improved liver function, glucose plasma level, lipid profile, HOMA-IR, and histological manifestations of NASH.
2.1.2. Safety Aspects
2.2. Nicotinamide Riboside
2.2.1. Dosage
- ⮚
- Trammell et al. determined the time and dose-dependent effects of NR on blood NAD+ level in humans [39]. They reported that human blood level of NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study. They also demonstrated that single doses of 100, 300, and 1000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans.
- ⮚
- Airhart et al. recently reported an open-label, non-randomized study of the pharmacokinetics of NR and its effects on blood NAD+ levels [40]. In eight healthy volunteers, 250 mg NR was orally administered on days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on days 7 and 8. On the morning of day 9, subjects completed a 24-hour pharmacokinetic study after receiving 1000 mg NR at t = 0. They analyzed whole-blood levels of NR, clinical blood chemistry, and NAD+ levels and reported that oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). The authors concluded that NR increases circulating NAD+ in humans and it may be used in treatment of patients with diseases associated to mitochondrial dysfunction [40].
2.2.2. Safety Aspects
2.3. l-Serine
Dosage
- ⮚
- ⮚
- Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a disorder caused by missense mutations in the enzyme serine palmitoyltransferase (SPT) [44]. Subjects received daily supplements of powdered serine (mixed in water) on a low- or high-dose schedule (200 or 400 mg/kg body weight, respectively; n = 7 per group). Results showed that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of serine supplementation as a first treatment option for this disorder [44].
- ⮚
- In our previous study, we assessed the effect of dietary supplementation with serine (200 mg/kg per day) for 2 weeks on fatty liver and fasting levels of plasma markers of liver functions in six obese subjects with NAFLD. Our analysis showed that supplementation of serine improved markers of liver tissue function and significantly decreased liver fat [21].
- ⮚
- Fridman et al. performed a randomized, double-blind, placebo-controlled trial (n = 18) to evaluate the efficacy and safety of serine treatment for adults with hereditary sensory and autonomic neuropathy type 1 (HSAN1). The study subjects were randomized to serine (400 mg/kg/day) or placebo for one year. All participants received serine during the second year. Analysis of vital signs, physical examination findings, and clinical laboratory examinations did not reveal adverse effects of serine. Thus, long-term serine supplementation did not reveal adverse effects of serine [45].
2.4. N-Acetyl-L-Cysteine
2.4.1. Dosage
- ⮚
- In early psychosis, NAC was administered at a dose of 2700 mg/day for 6 months in a double-blind placebo-controlled trial [48].
- ⮚
- NAC was administered to enhance performance of elite sport. A recent systematic review of the literature evaluated the effect of NAC supplementation. The typical daily dose of NAC reported was 5.8 g/day; with a range between 1.2 and 20.0 g/day [49].
- ⮚
- The effect of NAC supplementation on oxidative stress status and alveolar inflammation was analyzed in a double-blind, randomized clinical trial using a dose of 1800 mg/day for 4 months in people exposed to asbestos [50].
- ⮚
- NAC was administered in oral doses of 6000–8000 mg daily for several months in HIV-infected patients. It had a good safety profile and minimal adverse effects [51].
- ⮚
- NAFLD patients (n = 30) were randomly selected to receive either NAC (600 mg per 12 h) or vitamin C (1000 mg per 12 h) [52]. Liver function tests (ALT, AST and ALP) were measured as well as the grade of steatosis, the pattern of its echogenicity, the span of the liver and the spleen, and the portal vein diameter before the intervention. Patients were followed up using the same method of evaluation repeated in the first, second, and third months. NAC resulted in a significant decrease of serum ALT after three months, compared to vitamin C. This effect was independent of the grade of steatosis in the initial diagnosis. It has been reported that NAC significantly decrease the span of the spleen and it can be used to improve liver function in patients with NAFLD [52].
- ⮚
- The therapeutic effect of NAC in the treatment of NASH was investigated in 35 patients diagnosed with NASH based on liver biopsy. Patients were divided into two groups: the first (18 patients) was administered NAC 600 mg/day orally for 4 weeks, while the control group (17 patients) was followed up without therapy. Results did not show improved liver function in this study. It has been reported that the daily amount of glutathione synthesis in humans is 10–15 g and most of the sources of this are provided from the natural sources of the organism. Therefore, the authors hypothesized that the lower dosage of NAC (600 mg/day) might not affect glutathione synthesis to a great extent [53].
- ⮚
- To test whether glutathione deficiency occurs due to the diminishd synthesis and contributes to oxidative stress, eight elderly (60–75 years) and eight younger (30–40 years) subjects received stable-isotope infusions of [2H(2)]glycine, after which red blood cell (RBC) glutathione synthesis and concentrations, plasma oxidative stress, and markers of oxidant damage were measured. Results showed that glutathione deficiency in elderly humans occurs because of a marked reduction in synthesis, and that dietary supplementation with the two glutathione precursors cysteine (as NAC) and glycine fully restores glutathione synthesis and concentrations and lowers levels of oxidative stress and oxidant damages [54].
2.4.2. Safety Aspects
3. Conclusions
Supplementary Materials
Funding
Acknowledgments
Conflicts of Interest
References
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---|---|---|---|---|
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NCT01835782 | Determining the Safety of l-serine in ALS | 1–30 g/day | Amyotrophic Lateral Sclerosis (ALS) | Phase 1|Phase 2 |
NCT03580616 | Tolerability and Efficacy of l-Serine in Patients With Amyotrophic Lateral Sclerosis (ALS) | 30 g/day | Amyotrophic Lateral Sclerosis | Phase 2 |
NCT01733407 | l-Serine Supplementation in Hereditary Sensory Neuropathy Type 1 | 0.4 g/kg/day | Hereditary Sensory and Autonomic Neuropathy Type I | Phase 1|Phase 2 |
NCT02599038 | Serine Supplementation for Obese Subjects With Fatty Liver Disease | 0.2 g/kg/day | Non-alcoholic Fatty Liver Disease | Phase 1|Phase 2 |
l-carnitine (Completed Studies) | ||||
NCT03953248 | l-Carnitine as an Adjuvant Treatment in Acute Phosphide Poisoning (LC) | 1000 mg/8 h | Toxicity | Early Phase 1 |
NCT02281253 | Effects of a Bakery Product Enriched With Fibre and l-carnitine on Insulin Resistance in Patients With Metabolic Syndrome | 2325 mg/day | Metabolic X Syndrome|Overweight|Dyslipidemias | Not Applicable |
NCT03008356 | l-carnitine for Fatigue in COPD | 2000 mg/day | Copd|Fatigue | Phase 2|Phase 3 |
NCT00809042 | Combination Therapy of Hydroxyurea With l-Carnitine and Magnesium Chloride in Thalassemia Intermedia | 250 mg/day | β-Thalassemia Intermedia | Phase 2 |
NCT00386971 | Effects of l-Carnitine on Postprandial Clearance of Triglyceride-rich Lipoproteins in HIV Patients on HAART | 3000 mg/day | Hyperlipidemia|HIV Infections | Not Applicable |
NCT03476356 | l-Carnitine and Clomiphene Citrate for Induction of Ovulation in Women With Polycystic Ovary Syndrome | 3000 mg/day | Polycystic Ovary Syndrome | Not Applicable |
NCT01580553 | The Clinical Study of the Efficacy and Safety of l-Carnitine Injection in Treatment of Heart Failure | 1000 mg/day | Heart Failure, | Phase 2|Phase 3 |
NCT03630341 | Adding l-Carnitine to Clomiphene Citrate for Induction of Ovulation in Women With Polycystic Ovary Syndrome | 1000 mg/day | Polycystic Ovary Syndrome | Phase 4 |
NCT00247975 | Ability of l-carnitine to Prevent Heart Damage in Breast Cancer Patients Receiving Anthracycline Chemotherapy | 3000 mg/day | Heart Failure | Phase 2|Phase 3 |
NCT00822172 | Evaluation of Cilostazol in Combination With l-Carnitine | 2000 mg/day | Peripheral Vascular Disease | Phase 4 |
NCT01769157 | Effects of l-carnitine on Hypothyroidism | 1980 mg/day | Hypothyroidism | Phase 4 |
NCT01232907 | The Effects of l-carnitine on Fatigue in Spinal Cord Injury | 1980 mg/day | Spinal Cord Injury (SCI) | Phase 2 |
NCT00841295 | Effects of Parenteral l-carnitine Supplementation in Premature Neonates | 10 mg/kg/day | Complication of Prematurity | Not Applicable |
NCT02692235 | Carnitine Supplementation and Skeletal Muscle Function | 1500 mg/day | Sarcopenia | Phase 3 |
NCT01149525 | Efficacy of l-carnitine Versus Placebo in the Treatment of Fatigue in Multiple Sclerosis | 4000 mg/day | Multiple Sclerosis | Phase 3 |
NCT02322697 | Effect of Carnitine on Uremic Cardiomyopathy | 1000 mg/dialysis | Disorder of Fatty Acid Metabolism | Not Applicable |
NCT00351234 | Carnitine Levels and Carnitine Supplementation in Type I Diabetes | 100 mg/kg | Diabetes Mellitus, Type I|Hypoglycemia | Not Applicable |
NCT03907592 | Effect of Carnitine tartrate Supplementation and Resistance Training on Skeletal Muscle Function | 1000 mg/day | Sarcopenia | Not Applicable |
NCT01278693 | Effect of Oral l-carnitine Supplement on Lipid Profile, Anemia, and Quality of Life of Patients | 1000 mg/day | Complication of Hemodialysis | Phase 2 |
NCT01665092 | Rapid Administration of Carnitine in sEpsis | 6000–18000 mg/day | Septic Shock | Phase 2 |
NCT00227266 | Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy | 1000–10000 mg/day | Spinal Muscular Atrophy | Phase 2 |
NCT00079599 | l-Carnitine to Treat Fatigue in AIDS Patients | 500–3000 mg/day | HIV Infections|AIDS | Phase 2 |
NCT01819701 | l-carnitine and Coenzyme Q10 in Relation to the Oxidative Stress, Antioxidant Enzymes Activities, Inflammation, and the Risk of CAD | 1000–2000 mg/day | Coronary Artery Disease | Phase 2|Phase 3 |
NCT00091169 | Levocarnitine in Treating Fatigue in Cancer Patients | 500–1000 mg/day | Fatigue | Phase 3 |
Combined Metabolic Cofactors | ||||
NCT03838822 | Kinetics of Metabolic Cofactors (serine, NR, carnitine and NAC) in NAFLD | Serine: 20 g/day NAC: 5 g/day Carnitine: 3 g/day NR: 1 g/day | Healthy | Phase 1 |
EudraCT_2018-000894-59 | Supplementation of Metabolic Cofactors (serine, NR, carnitine and NAC) in treatment of NAFLD | Serine: 12.35–24.7 g/day NAC: 2.55–5.1 g/day Carnitine tartrate (%73Carnitine): 3.73–7.46 g/day NR: 1–2 g/day | NAFLD | Phase 2 |
NCT0XXXXX | Supplementation of Metabolic Cofactors (serine, NR, carnitine and NAC) in treatment of NAFLD | Serine: 12.35–24.7 g/day NAC: 2.55–5.1 g/day Carnitine tartrate (%73Carnitine): 3.73–7.46 g/day NR: 1–2 g/day | Parkinson Disease & Alzheimer Disease | Phase 2 |
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Mardinoglu, A.; Ural, D.; Zeybel, M.; Yuksel, H.H.; Uhlén, M.; Borén, J. The Potential Use of Metabolic Cofactors in Treatment of NAFLD. Nutrients 2019, 11, 1578. https://doi.org/10.3390/nu11071578
Mardinoglu A, Ural D, Zeybel M, Yuksel HH, Uhlén M, Borén J. The Potential Use of Metabolic Cofactors in Treatment of NAFLD. Nutrients. 2019; 11(7):1578. https://doi.org/10.3390/nu11071578
Chicago/Turabian StyleMardinoglu, Adil, Dilek Ural, Mujdat Zeybel, Hatice Hilal Yuksel, Mathias Uhlén, and Jan Borén. 2019. "The Potential Use of Metabolic Cofactors in Treatment of NAFLD" Nutrients 11, no. 7: 1578. https://doi.org/10.3390/nu11071578
APA StyleMardinoglu, A., Ural, D., Zeybel, M., Yuksel, H. H., Uhlén, M., & Borén, J. (2019). The Potential Use of Metabolic Cofactors in Treatment of NAFLD. Nutrients, 11(7), 1578. https://doi.org/10.3390/nu11071578