Pharmacological ER stress promotes hepatic lipogenesis and lipid droplet formation

American Journal of Translational Research (Impact Factor: 3.4). 01/2012; 4(1):102-13.
Source: PubMed


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 coacti-vator 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.

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Available from: Zeng-Quan Yang, Jul 03, 2014
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    • "* Indicates P b 0.05 compared with the day 1 time point. mRNA, can dramatically enhance the expression of PPAR-γ in Huh-7 cells [16], we hypothesize that XBP-1 may also be responsible for PPAR-γ expression observed in KO cells. "
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    ABSTRACT: c-Flip proteins are well-known apoptosis modulators. They generally contribute to tissue homeostasis maintenance by inhibiting death-receptor-mediated cell death. In the present manuscript, we show that c-Flip knock-out (KO) mouse embryonic fibroblasts (MEFs) kept in culture under starvation conditions gradually modify their phenotype and accumulate vacuoles, becoming progressively larger according to the duration of starvation. Large vacuoles are present in KO MEFs though not in WT MEFs, and are Oil red-O positive, which indicates that they represent lipid droplets. Western blot experiments reveal that, unlike WT MEFs, KO MEFs express high levels of the lipogenic transcription factor PPAR-γ. Lipid droplet accumulation was found to be associated with endoplasmic reticulum (ER) stress activation and autophagic modulation valuated by means of BIP increase , LC3 lipidation and AMP-activated protein kinase (AMPK) phosphorylation, and p62 accumulation. Interestingly, XBP-1, an ER stress-induced lipogenic transcription factor, was found to preferentially localize in the nucleus rather than in the cytoplasm of KO MEFs. These data demonstrate that, upon starvation, c-Flip affects lipid accumulation, ER stress and autophagy, thereby pointing to an important role of c-Flip in the adaptive response and ER stress response programs under both normal and pathological conditions. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 03/2015; 2012(7). DOI:10.1016/j.bbalip.2015.02.018 · 5.16 Impact Factor
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    • "For example, Tunicamycin (TM), a widely used ER stress inducer, is a nucleoside antibiotics that blocks N-linked glycosylation, causing accumulation of unfolded or misfolded proteins in the ER lumen. Injection of TM into mice results in ER stress-mediated liver steatosis and lipogenesis (Zhang et al., 2011; Lee et al., 2012a, b). These findings indicate the potential pathological role of ER stress in the development of hepatic steatosis. "
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    ABSTRACT: As an adaptive response to the overloading with misfolded proteins in the endoplasmic reticulum (ER), ER stress plays critical roles in maintaining protein homeostasis in the secretory pathway to avoid damage to the host. Such a conserved mechanism is accomplished through three well-orchestrated pathways known collectively as unfolded protein response (UPR). Persistent and pathological ER stress has been implicated in a variety of diseases in metabolic, inflammatory, and malignant conditions. Furthermore, ER stress is directly linked with inflammation through UPR pathways, which modulate transcriptional programs to induce the expression of inflammatory genes. Importantly, the inflammation induced by ER stress is directly responsible for the pathogenesis of metabolic and inflammatory diseases. In this review, we will discuss the potential signaling pathways connecting ER stress with inflammation. We will also depict the interplay between ER stress and inflammation in the pathogenesis of hepatic steatosis, inflammatory bowel diseases and colitis-associated colon cancer.
    Frontiers in Genetics 07/2014; 5:242. DOI:10.3389/fgene.2014.00242
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    • "Previous studies have shown that disruption of ER functions leads to the accumulation of intracellular lipids [26–28]. Disrupted protein glycosylation or ER-associated protein degradation by ER stress-inducing reagents, such as tunicamycin and brefeldin, has been demonstrated to increase LD accumulation in budding yeast Saccharomyces cerevisiae or mammalian cells [28, 29]. Previously, it is known that intracellular LD formation is through the lipogenic program activated by sterol regulatory element-binding proteins (SREBPs). "
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    ABSTRACT: Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic β cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic β cell is the only insulin-secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper function of insulin signaling. Accumulating evidence suggests that deleterious ER stress and excessive intracellular lipids in nonadipose tissues, such as myocyte, cardiomyocyte, and hepatocyte, cause pancreatic β-cell dysfunction and peripheral insulin resistance, leading to type II diabetes. The excessive deposition of lipid droplets (LDs) in specialized cell types, such as adipocytes, hepatocytes, and macrophages, has been found as a hallmark in ER stress-associated metabolic diseases, including obesity, diabetes, fatty liver disease, and atherosclerosis. However, much work remains to be done in understanding the mechanism by which ER stress response regulates LD formation and the pathophysiologic role of ER stress-associated LD in metabolic disease. This paper briefly summarizes the recent advances in ER stress-associated LD formation and its involvement in type II diabetes.
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