Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis.

FGF19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analogue, is currently in clinical development for treating non-alcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling while ameliorating hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect, and that administration of an HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL-C and LDL-C in db/db mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for seven days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogues.