Because scavenger receptor class B type 1 is the cholesterol uptake liver receptor, whereas peroxisome proliferator-activated receptor gamma coactivator-1beta (PGC-1beta) and PGC-1alpha are critical for lipid synthesis and degradation, we investigated the roles of these signaling molecules in the actions of ethanol-polyunsaturated fatty acids and betaine on hepatosteatosis and steatohepatitis. Ethanol-polyunsaturated fatty acid treatment caused the following: i) hepatosteatosis, as evidenced by increased liver cholesterol and triglycerides, lipid score, and decreased serum adiponectin; ii) marked inhibition of scavenger receptor class B type 1 glycosylation, its plasma membrane localization, and its hepatic cholesterol uptake function; and iii) moderate steatohepatitis, as evidenced by histopathological characteristics, increased liver tumor necrosis factor alpha and IL-6, decreased glutathione, and elevated serum alanine aminotransferase. These actions of ethanol involved up-regulated PGC-1beta, sterol regulatory element-binding proteins 1c and 2, acetyl-CoA carboxylase (ACC), and HMG-CoA reductase mRNAs/proteins and inactive non-phosphorylated AMP kinase; and down-regulated silence regulator gene 1 and PGC-1alpha mRNA/proteins and hepatic fatty acid oxidation. Betaine markedly blunted all these actions of ethanol on hepatosteatosis and steatohepatitis. Therefore, we conclude that ethanol-mediated impaired post-translational modification, trafficking, and function of scavenger receptor class B type 1 may account for alcoholic hyperlipidemia. Up-regulation of PGC-1beta and lipid synthetic genes and down-regulation of silence regulator gene 1, PGC-1alpha, adiponectin, and lipid degradation genes account for alcoholic hepatosteatosis. Induction of proinflammatory cytokines and depletion of endogenous antioxidant, glutathione, account for alcoholic steatohepatitis. We suggest betaine as a potential therapeutic agent because it effectively protects against adverse actions of ethanol.
Varatharajalu, R., et al., Adverse Signaling of Scavenger Receptor Class B1 and PGC1s in Alcoholic Hepatosteatosis and Steatohepatitis, and Protection by Betaine in Rat. Am J Pathol, 2014
Saturday, May 24, 2014
Improvement of adipose tissue function may contribute to the hepatoprotective role of betaine in ALD
BACKGROUND AND PURPOSE: Overactive adipose lipolysis contributes to the pathogenesis of alcoholic liver disease (ALD), however, mechanisms remain to be elucidated. We previously reported that chronic alcohol drinking resulted in a hypomethylation status in adipose tissue. This study aims to investigate mechanistic involvement of adipose tissue hypomethylation in alcohol-induced lipolysis and whether its correction contributes to the well-established hepatoprotective effect of betaine in ALD.
EXPERIMENTAL APPROACH: Male C57BL/6 mice were divided into four groups and started on one of four treatments for five weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF), and AF supplemented with betaine (BT/AF). Betaine was supplemented in the liquid diet at a concentration of 0.5% (wt/vol.). Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and lipolytic response was determined.
KEY RESULTS: Betaine alleviated alcohol-induced hepatic pathological changes and rectified impaired adipose tissue methylation status, which is concomitant with attenuated lipolysis. In adipocytes, the induction of cellular hypomethylation activates lipolysis through a mechanism involving protein phosphatase 2A (PP2A) suppression, resulting from PP2A C subunit hypomethylation, leading to hormone-sensitive lipase (HSL) activation. In line with in vitro observations, reduced adipose tissue PP2A C subunit methylation and activity, as well as enhanced HSL activation, were observed in alcohol-fed mice. Betaine attenuated alcohol-induced adipose tissue PP2A suppression and HSL activation.
CONCLUSIONS AND IMPLICATIONS: Adipose tissue hypomethylation state contributes to alcohol-induced adipose tissue dysfunction and improvement of adipose tissue function may contribute to the hepatoprotective role of betaine in ALD.
Dou, X., et al., Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine supplementation in a mouse model of alcoholic liver disease. Br J Pharmacol, 2014
EXPERIMENTAL APPROACH: Male C57BL/6 mice were divided into four groups and started on one of four treatments for five weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF), and AF supplemented with betaine (BT/AF). Betaine was supplemented in the liquid diet at a concentration of 0.5% (wt/vol.). Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and lipolytic response was determined.
KEY RESULTS: Betaine alleviated alcohol-induced hepatic pathological changes and rectified impaired adipose tissue methylation status, which is concomitant with attenuated lipolysis. In adipocytes, the induction of cellular hypomethylation activates lipolysis through a mechanism involving protein phosphatase 2A (PP2A) suppression, resulting from PP2A C subunit hypomethylation, leading to hormone-sensitive lipase (HSL) activation. In line with in vitro observations, reduced adipose tissue PP2A C subunit methylation and activity, as well as enhanced HSL activation, were observed in alcohol-fed mice. Betaine attenuated alcohol-induced adipose tissue PP2A suppression and HSL activation.
CONCLUSIONS AND IMPLICATIONS: Adipose tissue hypomethylation state contributes to alcohol-induced adipose tissue dysfunction and improvement of adipose tissue function may contribute to the hepatoprotective role of betaine in ALD.
Dou, X., et al., Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine supplementation in a mouse model of alcoholic liver disease. Br J Pharmacol, 2014
No association of betaine intake and peripheral artery disease
OBJECTIVE: Few studies have examined the roles of homocysteine and related nutrients in the development of peripheral artery disease (PAD). We examined the associations between plasma homocysteine, dietary B vitamins, betaine, choline, and supplemental folic acid use and incidence of PAD.
METHODS: We used two cohort studies of 72,348 women in the Nurses' Health Study (NHS, 1990-2010) and 44,504 men in the Health Professionals Follow-up Study (HPFS, 1986-2010). We measured plasma homocysteine in nested matched case-control studies of clinically recognized PAD within both cohorts, including 143 PAD cases and 424 controls within the NHS (1990-2010) and 143 PAD cases and 428 controls within the HPFS (1994-2008). We examined the association between diet and risk of incident PAD in the cohorts using a food frequency questionnaire and 790 cases of PAD over 3.1 million person-years of follow-up.
RESULTS: Higher homocysteine levels were positively associated with risk of PAD in men (adjusted IRR 2.17; 95% CI, 1.08-4.38 for tertile 3 vs. 1). There was no evidence of an association in women (adjusted IRR 1.14; 95% CI, 0.61-2.12). Similarly, higher folate intake, including supplements, was inversely associated with risk of PAD in men (adjusted HR 0.90; 95% CI, 0.82-0.98 for each 250 mug increase) but not women (HR 1.01, 95% CI, 0.88-1.15). Intakes of the other B vitamins, betaine, and choline were not consistently associated with risk of PAD in men or women.
CONCLUSION: Homocysteine levels were positively associated and dietary folate intake was inversely associated with risk of PAD in men but not in women.
Bertoia, M.L., et al., Plasma homocysteine, dietary B vitamins, betaine, and choline and risk of peripheral artery disease. Atherosclerosis, 2014. 235(1): p. 94-101
METHODS: We used two cohort studies of 72,348 women in the Nurses' Health Study (NHS, 1990-2010) and 44,504 men in the Health Professionals Follow-up Study (HPFS, 1986-2010). We measured plasma homocysteine in nested matched case-control studies of clinically recognized PAD within both cohorts, including 143 PAD cases and 424 controls within the NHS (1990-2010) and 143 PAD cases and 428 controls within the HPFS (1994-2008). We examined the association between diet and risk of incident PAD in the cohorts using a food frequency questionnaire and 790 cases of PAD over 3.1 million person-years of follow-up.
RESULTS: Higher homocysteine levels were positively associated with risk of PAD in men (adjusted IRR 2.17; 95% CI, 1.08-4.38 for tertile 3 vs. 1). There was no evidence of an association in women (adjusted IRR 1.14; 95% CI, 0.61-2.12). Similarly, higher folate intake, including supplements, was inversely associated with risk of PAD in men (adjusted HR 0.90; 95% CI, 0.82-0.98 for each 250 mug increase) but not women (HR 1.01, 95% CI, 0.88-1.15). Intakes of the other B vitamins, betaine, and choline were not consistently associated with risk of PAD in men or women.
CONCLUSION: Homocysteine levels were positively associated and dietary folate intake was inversely associated with risk of PAD in men but not in women.
Bertoia, M.L., et al., Plasma homocysteine, dietary B vitamins, betaine, and choline and risk of peripheral artery disease. Atherosclerosis, 2014. 235(1): p. 94-101
Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of colorectal cancer
BACKGROUND: Disturbances in one carbon-metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low.
SUBJECTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1,367 incident CRC cases (965 colon; 402 rectum) and 2,323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for CRC risk were estimated by conditional logistic regression comparing the fifth to the first quintile of plasma concentrations.
RESULTS: Overall, methionine (OR: 0.79, 95%CI: 0.63-0.99, P-trend=0.05), choline (OR: 0.77, 95%CI: 0.60-0.99, P-trend=0.07), and betaine (OR: 0.85, 95%CI: 0.66-1.09, P-trend=0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/L, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95%CI: 0.50-1.00, P-trend=0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95%CI: 0.43-0.88, P-trend=0.01). Plasma DMG was not associated with CRC risk.
CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of colorectal cancer.
Nitter, M., et al., Plasma Methionine, Choline, Betaine, and Dimethylglycine, in relation to Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol, 2014
SUBJECTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1,367 incident CRC cases (965 colon; 402 rectum) and 2,323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for CRC risk were estimated by conditional logistic regression comparing the fifth to the first quintile of plasma concentrations.
RESULTS: Overall, methionine (OR: 0.79, 95%CI: 0.63-0.99, P-trend=0.05), choline (OR: 0.77, 95%CI: 0.60-0.99, P-trend=0.07), and betaine (OR: 0.85, 95%CI: 0.66-1.09, P-trend=0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/L, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95%CI: 0.50-1.00, P-trend=0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95%CI: 0.43-0.88, P-trend=0.01). Plasma DMG was not associated with CRC risk.
CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of colorectal cancer.
Nitter, M., et al., Plasma Methionine, Choline, Betaine, and Dimethylglycine, in relation to Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol, 2014
Tuesday, May 6, 2014
Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms
Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects.
Cholewa, J.M., L. Guimaraes-Ferreira, and N.E. Zanchi, Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms. Amino Acids, 2014
Cholewa, J.M., L. Guimaraes-Ferreira, and N.E. Zanchi, Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms. Amino Acids, 2014
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