Transcriptomic and Proteomic analysis of clear cell foci (CCF) in the human non-cirrhotic liver identifies several differentially expressed genes and proteins with functions in cancer cell biology and glycogen metabolism

Abstract

Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen-overload and activation of AKT/mTOR-signaling. Here we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We mainly found genes and proteins with lower expression in CCF compared to control samples. Of 14 differentially expressed transcripts only 3 were overexpressed and belong to previously uncharacterized long non-coding RNAs. At the protein level, 3 proteins were at least 1.5-fold higher expressed in CCF than in control samples, while 22 proteins were at least 1.5-fold less abundant. Using immunohistochemistry, the reduced expressions of STBD1, USP28, monad/WDR92, CYB5B and HSPE1 were validated in CCF. Knockout of STBD1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have an effect on liver glycogen levels. Similiarly, Usp28 knockout in mice did not affect glycogen storage in diethylnitrosamine-induced liver carcinoma. Thus, these data indicate that reduced expression of STBD1 or USP28 in CCF is unlikely to explain glycogen overload. Our study revealed several novel proteins and RNAs that are differentially expressed in CCF and have functions relevant for carcinogenesis or the glycogen metabolism.

Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy

“…Interestingly, despite the report that liver Stbd1 is unchanged in Gaa-KO mice, Stbd1 KO prevents Gaa-KO–induced glycogen accumulation in the liver but not in skeletal muscle or heart tissues ( 46 ). In a separate study using otherwise healthy mice, Stbd1-KO did not affect liver glycogen content ( 50 ). In brown adipose tissue, Stbd1 and glycophagy may play a role in the link between lipid droplet biogenesis and glycogen dynamics.…”