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