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Am J Transl Res 2012;4(1):102-113
Original Article
Pharmacological ER stress promotes hepatic lipogenesis and lipid
droplet formation
Jin-Sook Lee, Roberto Mendez, Henry H. Heng, Zeng-quan Yang, Kezhong Zhang
Center for Molecular Medicine and Genetics, Department of Immunology and Microbiology, Karmanos Cancer
Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
Received December 30, 2011; accepted January 5, 2011; Epub January 6, 2011; Published January 15, 2012
Abstract: Endoplasmic Reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded
proteins in the ER lumen. A variety of biochemical stimuli or pathophysiologic conditions can directly or indirectly
induce ER stress, leading to activation of an ER-originated adaptive signaling response called Unfolded Protein
Response (UPR). Recent studies demonstrated that ER stress and UPR signaling are critically involved in the
initiation and progression of many diseases, such as metabolic disease, cardiovascular disease,
neurodegenerative disease, and cancer. In this study, we show that ER stress induced by pharmacologic
reagents, including tunicamycin (TM) and thapsigargin (Tg), promotes hepatic lipogenesis and lipid droplet
formation. Using quantitative gene expression analysis, we identified 3 groups of key lipogenic regulators or
enzymes that are inducible by pharmacological ER stress in a human hepatoma cell line Huh-7. These ER
stress-inducible lipogenic factors include: 1) lipogenic trans-activators including CCAAT/enhancer binding protein
alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator 1-alpha (PGC1α),
and Liver X receptor alpha (LXRα); 2) components of lipid droplets including fat-specific protein 27 (FSP27),
adipose differentiation related protein (ADRP), fat-inducing transcript 2 (FIT2), and adipocyte lipid-binding protein
(AP2); 3) key enzymes involved in de novo lipogenesis including acetyl-CoA carboxylase 1 (ACC1) and stearoyl-
CoA desaturase-1 (SCD1). Supporting the role of pharmacologic ER stress in up-regulating de novo lipogenesis,
TM or Tg treatment significantly increased accumulation of cytosolic lipid droplet formation in the hepatocytes.
Moreover, we showed that forced expression of an activated form of X-box binding protein 1 (XBP1), a potent UPR
trans-activator, can dramatically increase expression of PPARγ and C/EBPα in Huh-7 cells. The identification of
ER stress-inducible lipogenic regulators provides important insights into the molecular basis by which acute ER
stress promotes de novo lipogenesis. In summary, the findings from this study have important implication in
understanding the link between ER stress and metabolic disease. (AJTR1112005).
Keywords: Endoplasmic Reticulum (ER) stress, lipogenesis
Full Text PDF
Address all correspondence to:
Kezhong Zhang, PhD
Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
540 E. Canfield Avenue, Detroit, MI 48201, USA.
Tel: 313-577-2669; FAX: 313-577-5218
E-mail: kzhang@med.wayne.edu
Original Article
Pharmacological ER stress promotes hepatic lipogenesis and lipid
droplet formation
Jin-Sook Lee, Roberto Mendez, Henry H. Heng, Zeng-quan Yang, Kezhong Zhang
Center for Molecular Medicine and Genetics, Department of Immunology and Microbiology, Karmanos Cancer
Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
Received December 30, 2011; accepted January 5, 2011; Epub January 6, 2011; Published January 15, 2012
Abstract: Endoplasmic Reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded
proteins in the ER lumen. A variety of biochemical stimuli or pathophysiologic conditions can directly or indirectly
induce ER stress, leading to activation of an ER-originated adaptive signaling response called Unfolded Protein
Response (UPR). Recent studies demonstrated that ER stress and UPR signaling are critically involved in the
initiation and progression of many diseases, such as metabolic disease, cardiovascular disease,
neurodegenerative disease, and cancer. In this study, we show that ER stress induced by pharmacologic
reagents, including tunicamycin (TM) and thapsigargin (Tg), promotes hepatic lipogenesis and lipid droplet
formation. Using quantitative gene expression analysis, we identified 3 groups of key lipogenic regulators or
enzymes that are inducible by pharmacological ER stress in a human hepatoma cell line Huh-7. These ER
stress-inducible lipogenic factors include: 1) lipogenic trans-activators including CCAAT/enhancer binding protein
alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator 1-alpha (PGC1α),
and Liver X receptor alpha (LXRα); 2) components of lipid droplets including fat-specific protein 27 (FSP27),
adipose differentiation related protein (ADRP), fat-inducing transcript 2 (FIT2), and adipocyte lipid-binding protein
(AP2); 3) key enzymes involved in de novo lipogenesis including acetyl-CoA carboxylase 1 (ACC1) and stearoyl-
CoA desaturase-1 (SCD1). Supporting the role of pharmacologic ER stress in up-regulating de novo lipogenesis,
TM or Tg treatment significantly increased accumulation of cytosolic lipid droplet formation in the hepatocytes.
Moreover, we showed that forced expression of an activated form of X-box binding protein 1 (XBP1), a potent UPR
trans-activator, can dramatically increase expression of PPARγ and C/EBPα in Huh-7 cells. The identification of
ER stress-inducible lipogenic regulators provides important insights into the molecular basis by which acute ER
stress promotes de novo lipogenesis. In summary, the findings from this study have important implication in
understanding the link between ER stress and metabolic disease. (AJTR1112005).
Keywords: Endoplasmic Reticulum (ER) stress, lipogenesis
Full Text PDF
Address all correspondence to:
Kezhong Zhang, PhD
Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
540 E. Canfield Avenue, Detroit, MI 48201, USA.
Tel: 313-577-2669; FAX: 313-577-5218
E-mail: kzhang@med.wayne.edu
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