Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease

Abstract

BACKGROUND AND PURPOSEOveractive lipolysis in adipose tissue contributes to the pathogenesis of alcoholic liver disease (ALD); however, the mechanisms involved have not been elucidated. We previously reported that chronic alcohol consumption produces a hypomethylation state in adipose tissue. In this study we investigated the role of hypomethylation in adipose tissue in alcohol-induced lipolysis and whether its correction contributes to the well-established hepatoprotective effect of betaine in ALD. EXPERIMENTAL APPROACHMale C57BL/6 mice were divided into four groups and started on one of four treatments for 5 weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF) and AF supplemented with betaine (BT/AF). Betaine, 0.5% (w v −1 ), was added to the liquid diet. Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and their lipolytic responses determined. KEY RESULTSBetaine alleviated alcohol-induced pathological changes in the liver and rectified the impaired methylation status in adipose tissue, concomitant with attenuating lipolysis. In adipocytes, inducing hypomethylation activated lipolysis through a mechanism involving suppression of protein phosphatase 2A (PP2A), due to hypomethylation of its catalytic subunit, leading to increased activation of hormone-sensitive lipase (HSL). In line with in vitro observations, reduced PP2A catalytic subunit methylation and activity, and enhanced HSL activation, were observed in adipose tissue of alcohol-fed mice. Betaine attenuated this alcohol-induced PP2A suppression and HSL activation. CONCLUSIONS AND IMPLICATIONSIn adipose tissue, a hypomethylation state contributes to its alcohol-induced dysfunction and an improvement in its function may contribute to the hepatoprotective effects of betaine in ALD.

FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice

“…In the current study, our results showed that betaine supplementation decreased fatty acid synthesis and increased TG breakdown, which led to a decrease of hepatic lipid accumulation. These results are in line with previous studies which showed decreased TG content in the liver upon increasing betaine availability on adult mice [9,11]. In addition, studies also suggested that the effects of betaine on hepatic lipid deposition might also be through its ability to increase endogenous carnitine, as carnitine might increase carnitine palmitoyltransferase I-mediated fatty acid translocation into the mitochondria and β-oxidation [6,22].…”

“…In addition, studies also suggested that the effects of betaine on hepatic lipid deposition might also be through its ability to increase endogenous carnitine, as carnitine might increase carnitine palmitoyltransferase I-mediated fatty acid translocation into the mitochondria and β-oxidation [6,22]. Recently, the effects of betaine on the rectification of DNA methylation have also been declared to be a major mechanism accounting for the hepatoprotective effects of betaine [9,30]. These effects of betaine were mostly due to its role in one-carbon metabolism as a methyl donor.…”

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“…33 Furthermore, we provided evidence supporting that intracellular hypomethylation status in adipocytes in the setting of chronic alcohol feeding contributes to adipose tissue hyper-lipolytic response in ALD via suppressing protein phosphatase 2A(PP2A) activity, leading to hormone sensitive lipase over activation (Figure 2). 34 Our data support that rectification of methionine metabolism through dietary supplementation of betaine protects against alcohol-induced liver damage, at least partially via improving adipose tissue function. Taken together, the recent research in our group suggests that aberrant methionine metabolism in adipocytes contributes to alcohol-elicited adipose tissue dysfunction and liver damage.…”

Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease

“…Further studies have reported that alcohol-induced decreases in the adipose SAM:SAH ratio and elevations in homocysteine levels [155, 156, 158, 159] enhances HSL activation to promote LD lipolysis [158–160]. More importantly, betaine exerts it therapeutic effect to facilitate TAG storage in adipocytes by preventing these ethanol-induced changes in adipose tissue [158, 159].…”