TABLE 2.

A summary of the health implications of betaine with molecular mechanisms.

Disease	Effect of betaine	Molecular mechanism	References
Homocystinuria	Lowers plasma tHcy levels	Promotion of methionine-homocysteine cycle	Craig (2004)
Cardiovascular disease	Lowers plasma tHcy levels	Promotion of methionine-homocysteine cycle	Schwab et al. (2006), Olthof et al. (2016)
	Reduction of inflammation	Lowers the C-reactive protein, IL-6, and TNF-α	Detopoulou et al. (2008), Lv et al. (2009)
Liver disease (Alcoholic and non-alcoholic fatty liver disease)	Suppresses hepatic lipid synthesis	suppression of DGAT1, DGAT2, SREBP-1c, SREBP-2, fatty acid synthase, and HMG-CoA reductase and upregulation of PGC-1α in the liver	Yang et al. (2017)
	Enhances fatty acid oxidation	Increase of the expression of CPT1, PPARα, FGF21, and AMPK in the liver	Li et al. (2015b)
	Promotes VLDL synthesis and release	Increase of hepatic SAM/SAH ratio and promotes one-carbon metabolism and synthesis of phosphatidylcholine	Barak et al. (1997), Deminice et al. (2015)
		Enhances BHMT expression and promotion of hepatic PC synthesis	Li et al. (2015b)
	Alleviates hyperhomocysteinemia	Promotion of methionine-homocysteine cycle	Kenyon et al. (1998), Stickel et al. (2000)
	Reduction of oxidative stress	Increase in cellular reduced glutathione levels	Jung et al. (2013), Zakhari (2013), Kim et al. (2017)
	Reduces ER stress	Attenuation of GRP78, CHOP, and JNK activation	Kaplowitz and Ji (2006), Wang et al. (2010)
	Inhibition of inflammatory response	Suppression of NLRP3 inflammasome activation	Kim et al. (2017)
		Inhibition of IL-1β production and release	Xia et al. (2018), Zhao et al. (2018)
		Induction of IL-10 and decreasing TNF and IL-6 expression	Veskovic et al. (2019)
	Improves adipocyte functions	Increase in mitochondrial biogenesis	Du et al. (2018)
		Corrects aberrant adipokine production	Wang et al. (2010)
	Improves insulin resistance	Activation of IRS1, PKB/Akt, and AMPK	Kathirvel et al. (2010); Du et al. (2018)
	Modulate epigenetic modifications	Increase of SAM/SAH ratio and restore methylation capacity; Downregulation of fatty acid synthase and upregulation of fatty acid oxidation (ACOX, PPARα, AMPK, FGF10, ATGL)	Wang et al. (2014); Chen et al. (2021)
		Increase in mitochondrial content and activity	Zhang et al. (2019)
	Inhibits apoptosis	Reduction of Bax and induction of Bcl-2	Veskovic et al. (2019)
		Activation of Akt/mTOR signaling	Veskovic et al. (2019)
	Activates autophagy	Increases the expression of beclin 1, Atg4, and Atg5	Veskovic et al. (2019)
Neurological disorders	Enhances neuronal mitochondrial respiration	Modulation of histone H3 trimethylation on Lys 4 (H3K4me3) in neurons	Singhal et al. (2020)
	Promotes oligodendrocyte maturation	Modulation of DNA methylation and increases the expression of oligodendrocyte maturation genes SOX10 and NKX-2.2	Sternbach et al. (2021)
	Prevents oxidative stress	Enhancement of glutathione peroxidase activity	Alirezaei et al. (2011)
	Mitigates hyperhomocysteinemia in Alzheimer’s disease	Attenuation of tau hyperphosphorylation and Aβ production	Chai et al. (2013)