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Cyclin D1 regulates adipose triglyceride lipase (ATGL) to influence hepatic lipid droplet metabolism and cell proliferation
Author(s) -
Ploeger Jonathan,
Kamarajugadda Sushama,
Mashek Douglas,
Albrecht Jeffrey H
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.871.1
Subject(s) - adipose triglyceride lipase , cyclin d1 , gene knockdown , cell cycle , chemistry , cell growth , medicine , endocrinology , biology , microbiology and biotechnology , adipose tissue , cell , biochemistry , apoptosis , lipolysis
Obesity is well‐documented to promote the development of nonalcoholic fatty liver disease including its more advanced stages such as non‐alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. Cyclin D1 (D1) is a cell cycle protein that regulates G1/S transition, the rate‐limiting step in cell division. D1 is highly expressed in liver cancer and its overexpression (OE) leads to lipid droplet (LD) accumulation in hepatocytes. Liver‐specific knockdown of adipose triglyceride lipase (ATGL), the rate‐limiting enzyme in triglyceride (TG) catabolism, promotes LD accumulation. In order to characterize a potential link between D1 and ATGL we employed studies in primary hepatocytes and mouse immortalized AML12 cells. As expected, in the absence of mitotic stimuli, D1 OE was sufficient to drive DNA synthesis in primary hepatocytes. However, these effects are abrogated with ATGL. Knockdown of D1 in the presence of mitogens inhibited DNA synthesis and increased ATGL mRNA expression, but knockdown or chemical inhibition of ATGL recovered DNA synthesis. Moreover, cell cycle analysis using flow cytometry confirmed that D1 knockdown increased accumulation of cells in the G0/G1 phase and reduced cells in the S and G2/M phase; these results were reversed with ATGL knockdown or chemical inhibition. Taken together, these data illustrates for the first time that cyclin D1 regulates ATGL to alter hepatic LD metabolism and proliferative capacity in primary hepatocytes and AML12 cells. Support or Funding Information This project was supported by NIDDK (DK054921) to JHA and (DK085008) to DGM, NCI T32CA132670 to JMP and the Minnesota Obesity Center (DK050406).