Figure 3.

Conjugated bile acids regulate sterol and lipid metabolism via activating S1PR2. In hepatocytes, CBA activates the S1PR2 on the cell membrane, which induces the activation of ERK1/2 through activation of Gi protein. Activation of Gi will further induce activation of SRC, which can activate the matrix metalloproteinase (MMP) and EGFR. EGFR-induced ERK1/2 activation can directly activate gene transcription in the nucleus or further induce the activation of nuclear SPHK2 and the increase of nuclear S1P levels. Nuclear S1P is a strong inhibitor of nuclear HDAC1/2. Inhibition of HDAC will increase the acetylation and transcription of a lot of genes involved in nutrient and lipid metabolism such as CYP7A1, SREBP1c and ApoB-100.