Decrease in UCP1 by sustained high lipid promotes NK cell necroptosis to exacerbate nonalcoholic liver fibrosis

Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1^-/- mice (8-10 weeks old), impaired NK cell bioactivity was shown in methionine-choline-diet (MCD)-fed UCP1^-/- mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1^flox/flox-NCR1^cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1^-/- NK cells. Transcriptions of mitophagy-associated molecules in UCP1^-/- NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NK^WT cells, PA-treated NK^WT cells, or physiologic NK^KO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1^S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 μM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.