| SREBP, a master regulator of lipogenesis, is often considered to be involved in NASH and HCC development. However, in JDDW 2019, we reported that inhibition of SREBP pathway by additional knockout of SREBP activating protein SCAP in PTEN KO mice (PTEN/SCAP DKO) unexpectedly exacerbated liver injury, fibrosis, and carcinogenesis. Here, we analyzed molecular mechanisms why inhibition of lipogenesis rather exacerbated liver injury in PTEN KO mice. Restoration of SREBP activity in PTEN/SCAP DKO mice markedly improved liver injury, confirming that SREBP-mediated lipogenic pathway plays a protective role in PTEN KO mice. Transcriptome analysis revealed significant upregulation of ER stress pathway in PTEN/SCAP DKO mice and induction of chaperon protein GRP78 to PTEN/SCAP DKO liver significantly attenuated ER stress and liver injury, indicating the pivotal role of ER stress in this phenotype. In comprehensive lipidomic analysis, fatty acid composition of phosphatidylcholine was drastically altered in PTEN/SCAP DKO mice. Especially, phosphatidylcholines containing long-chain polyunsaturated fatty acids which play important roles in ER membrane fluidity were significantly decreased in PTEN/SCAP DKO liver and also in ER fraction. Notably, administration of phosphatidylcholine cocktail to PTEN/SCAP DKO mice significantly improved liver injury. Thus, strong inhibition of lipogeneis in stressed liver possibly exacerbates liver injury through disturbance of phospholipid metabolism. |
