Linking liver metabolic and vascular disease via bile acid signaling

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder affecting over one quarter of the global population. Liver fat accumulation in NAFLD is promoted by increased de novo lipogenesis leading to the development of a proatherosclerotic lipid profile and atherosclerotic cardiovascular disease (CVD). The CVD component of NAFLD is the main determinant of patient outcome. The farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) are bile acid-activated receptors that modulate inflammation and lipid and glucose metabolism in the liver and CV system, and are thus potential therapeutic targets. We review bile acid signaling in liver, metabolic tissues, and the CV system, and we propose the development of dual FXR/GPBAR1 ligands, intestine-restricted FXR ligands, or statin combinations to limit side effects and effectively manage the liver and CV components of NAFLD.