Retinoid X receptor aLiver fibrosis a b s t r a c t Hepatic stellate cells (HSCs) activation is an initial event in liver fibrosis. MicroRNAs (miRNAs) have been found to play essential roles in cell differentiation, proliferation, and fat metabolism. In this study, we showed that down-regulation of two over-expressed miRNAs, miR-27a and 27b allowed culture-activated rat HSCs to switch to a more quiescent HSC phenotype, with restored cytoplasmic lipid droplets and decreased cell proliferation. Mechanistically, retinoid X receptor a was confirmed to be the target of miR-27a and 27b. These results indicated a new role and mechanism of miR-27a and 27b in regulating fat metabolism and cell proliferation during HSCs activation.

The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation and xenograft tumorigenicity Surprisingly, FBXO22 suppressed epithelial-mesenchymal transition (EMT), cell motility, and invasiveness and metastatic lung colonization Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1-Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression. These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis. .

Graphical Abstract Highlights d Pore-forming agents evoke calcium-dependent lipid scrambling in the plasma membrane d This effect promotes plasma membrane repair and is mediated by lipid scramblase TMEM16F d TMEM16F induces repair by facilitating release of extracellular vesicles d TMEM16F-deficient mice display greater susceptibility to Listeria monocytogenes

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Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress.