Betaine in ameliorating alcohol-induced hepatic steatosis

Abstract

Alcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and/or activities of protein phosphtase-2A, FOXO1, PPAR-α, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring β-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine's effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine's remedial properties to treat alcohol-induced hepatic steatosis.

Keywords: AALD; Alcohol; Alcohol-associated liver disease; Alcoholic liver disease; Betaine; Fatty liver; Steatosis.

Fig. 1

Alcohol-induced impairment of methionine cycle and betaine-mediated repair. Methylation is essential for normal body functionality and homeostasis. Methionine metabolism/cycle is central to this process as it generates methyl-group donors. a Alcohol hampers methionine cycle by increasing or decreasing levels/activities of various components of this cycle, eventually leading to hepatic lipid accumulation. b Betaine repairs the alcohol-induced alterations and thereby attenuates lipid accumulation in the liver. BHMT betaine-homocysteine methyltransferase, PC phosphatidylcholine, PE Phosphatidylethanolamine N-methyltransferase, PEMT Phosphatidylethanolamine N-methyltransferase, SAH S-adenosylhomocysteine, SAM S-adenosylmethionine, VLDL very-low density lipoprotein

Fig. 2

Betaine-mediated methylation of epinephrine. Betaine-mediated methylation of norepinephrine to epinephrine increases the levels of NAD +, which can fuel the catalytic conversion of alcohol to acetaldehyde by alcohol dehydrogenase. Thus, betaine can aid in eliminating alcohol by providing methyl groups to norepinephrine

Fig. 3

Core events and factors of alcohol-induced hepatic steatosis and betaine-mediated amelioration. Key interrelated events and factors that cause alcohol-induced excess hepatic triglyceride accumulation are depicted. Alcohol-induced events include (i) increased hepatic de novo lipogenesis, (ii) decreased/hindered mitochondrial fatty acid oxidation, (iii) reduced synthesis and secretion of VLDL, and (iv) increased hepatic uptake of adipose-tissue-derived free fatty acids. There are several mechanisms and factors that facilitate these events. This figure also shows selected mechanisms of betaine-mediated amendments to these alcohol-induced effects. Interestingly, alcohol metabolism generates excessive amount of malonyl-CoA. This inhibits mitochondrial carnitine palmitoyl transferase-1 [25], the enzyme essential for β-oxidation of fatty acids, thereby contributing to alcohol-induced impairment in fatty acid oxidation. Dotted line indicates the relation between AMPK and acetyl-CoA carboxylase; activation of AMPK deactivates (phosphorylates) acetyl-CoA carboxylase and thereby partly inhibits hepatic fatty acid synthesis [34]. Yellow star with question reflects the apparent contradiction between alcohol-induced increment in activity of PP2A and alcohol-induced decrease in methylation of PP2A, which needs further investigation. AMPK AMP-activated protein kinase, PP2A Protein phosphatase-2A, PPAR Peroxisome proliferator activated receptor, SAH S-adenosylhomocysteine, SAM S-adenosylmethionine, SREBP Sterol regulatory element binding protein, VLDL Very-low density lipoprotein