Engineered FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis

Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.

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Zhou M, Learned RM, Rossi SJ, Tian H, DePaoli AM, Ling L