Fig. 8.

Possible molecular mechanisms of GRAMD1B and SPTLC2 involving in PCOS. (A) GRAMD1s comprise an N-terminal GRAM domain and a StART-like domain, which is followed by a C-terminal transmembrane domain that anchors the protein to the ER. GRAMD1s move to ER-PM (plasma membrane) contacts by sensing accessible PM cholesterol via the GRAM domain and can transport accessible cholesterol from the PM to the ER via the StART-like domain. GRAMD1s family are important for cholesterol homeostasis. GRAMD1B protein presented a downregulated level in FF-EVs of PCOS patients. Simultaneously, gramd1b gene is the predicted targets of 5 DEmiRNAs, including has-mir-3131, has-mir-206, has-mir-204-5p, has-mir-100-5p, and has-mir-193a-5p, found to be upregulated in FF-EVs of PCOS patients. An imagined work scenario should be decreased GRAMD1 expression or loss of GRAMD1 function caused by upregulated miRNAs led to sustained accumulation of accessible cholesterol in the PM and possible dysregulation of cellular cholesterol homeostasis as well as altered steroid hormone production and activity, eventually resulting in POCS. (B) SPT is a rate-limiting step in the de novo ceramide biosynthesis pathway and is composed of two main subunits, namely, Sptlc1 and Sptlc2. Increased ceramide subclasses have also been identified as novel lipidomic biomarkers in PCOS. High ceramide levels have been consistently linked with insulin resistance and the development of diabetes, suggesting that SPTLC2 is the key hub in PCOS