SREBP-1-independent regulation of lipogenic gene expression in adipocytes

Sekiya, Motohiro; Yahagi, Naoya; Matsuzaka, Takashi; Takeuchi, Yoshinori; Nakagawa, Yoshimi; Takahashi, Haruka; Okazaki, Hiroaki; Ikoma, Yoko; Ohashi, Ken; Gotoda, Takanari; Ishibashi, Shun; Nagai, Ryozo; Yamazaki, Tsutomu; Kadowaki, Takashi; Yamada, Nobuhiro; Osuga, Jun-ichi; Shimano, Hitoshi

doi:10.1194/jlr.m700033-jlr200

Cited by 115 publications

(99 citation statements)

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“…Previous reports demonstrated that expression of Srebp‐1c and its downstream target genes is upregulated and downregulated under fed and fasting conditions, respectively, in both the liver and WAT (Horton et al ., 1998; Sekiya et al ., 2007). However, we observed that CR enhanced expression of proteins involved in FA biosynthesis, via Srebp‐1c, in WAT, regardless of feeding condition.…”

Section: Discussionmentioning

confidence: 99%

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

et al. 2017

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SummaryCaloric restriction (CR) can delay onset of several age‐related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR‐associated metabolic remodeling of WAT remain unclear. Sterol regulatory element‐binding protein‐1c (Srebp‐1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp‐1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α (Pgc‐1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp‐1c, most of these CR‐associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp‐1c may be an important factor both for CR‐associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp‐1c, the primary FA biosynthesis‐promoting transcriptional factor implicated in fatty liver disease, is also the food shortage‐responsive factor in WAT. This indicated that Srebp‐1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

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Section: Discussionmentioning

confidence: 99%

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

et al. 2017

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“…LXR's role in hepatic lipogenesis is very well established; in this tissue, LXR induces lipid accumulation through stimulation of its target genes SREBP1c, fatty acid synthase (FAS), stearoyl-CoA (SCD1), and acyl cocarboxylase 1 (ACC1) ( 48,59 ). In adipose tissue, the story becomes less predictable, since LXR activation in wild-type mice is not accompanied by an increase in adipose tissue FAS, despite the expected increase in SREBP1c ( 60 ). In addition, although the obesity resistant LXR ␣ ␤ Ϫ / Ϫ mice exhibit the expected attenuation of expression of the lipogenic LXR target genes in the liver, in adipose tissue, these same genes are actually increased despite having smaller adipocytes ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

LXRα fuels fatty acid-stimulated oxygen consumption in white adipocytes

Dib

Bugge

Collins

2014

Journal of Lipid Research

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Key hormonal regulatory mechanisms that control the balance between lipogenesis and lipolysis in adipose tissue are disrupted. Obese individuals are less sensitive to the antilipolytic actions of insulin and display an increase in basal lipolytic activity in their white adipose tissue (WAT), which results in high circulating levels of FFAs ( 6 ). These chronically elevated FFAs have been implicated in the pathogenesis of insulin resistance and type 2 diabetes ( 7 ). Thus utilization and/or sequestration of FFAs in WAT before they enter the circulation represent an important protective mechanism.The break-down of TG into FFA and glycerol in both WAT and brown adipose tissue (BAT) are largely under the control of the sympathetic nervous system (SNS) via catecholamines ( 8-10 ), and also by cardiac natriuretic peptides ( 11 ). In BAT the liberated FFAs provide not only the substrate for mitochondrial oxidative phosphorylation but they also directly activate the brown adipocyte-specifi c mitochondrial protonophoric uncoupling protein 1 (UCP1). UCP1 disengages energy stored in the proton gradient from ATP synthesis, resulting in a form of energy wastage known as thermogenesis ( 10,12 ). The existence of BAT has recently been affi rmed in adult humans ( 13,14 ). In WAT, on the other hand, it has been traditionally accepted that most of the FFAs liberated by lipolysis are released into the circulation to provide substrate for the energy requirements of other tissues in the body, including muscle, heart, and BAT ( 15, 16 ). Recent evidence, however, indicates a higher mitochondrial content in WAT than previously believed ( 17, 18 ), suggesting a greater role for white adipocyte mitochondria in the regulation of whole-body physiology ( 19 ). In addition to being released into the circulation and, to a much lesser extent, being reesterifi ed in situ ( 20 ), a portion of the liberated FFA undergoes mitochondrial oxidation within WAT itself ( 18,21,22 ). Obesity, which is characterized by an excessive increase in adipose tissue mass, is an escalating threat of epidemic proportions ( 1 ) and is highly correlated with a plethora of metabolic disorders ( 2, 3 ). Adipose tissue is a very plastic organ that can expand or contract to accommodate the needs of the organism. In cases of excess energy intake, adipose tissue engages in lipogenesis to store this energy as triglyceride (TG), while in times of inadequate dietary sources, it breaks down its reserves through lipolysis to provide substrate for oxidation and ATP synthesis within other tissues ( 4 ). Both lipogenesis and lipolysis are tightly controlled in adipocytes ( 5 ). However, in the obese condition, the normal homeostatic balance between lipogenesis and lipolysis is altered due to the excess caloric load ( 5 ). Abbreviations: AT-WT, aP2-Cre negative fl oxed (mice); ATaKO, adipose tissue LXR ␣ knockout (mice); BAT, brown adipose tissue; HFD, high-fat diet; HSL, hormone-sensitive lipase; LXR, liver X receptor; OCR, oxygen consumption rate; SNS, sympathetic nervous system...

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“…It also decreased Glut 4, which is regulated by C/EBPa and FAS. Although SREBP-1c plays a critical role in the induction of FAS in hepatocyte (24), a recent study has revealed that SREBP-1c is not committed to the regulation of lipogenesis in adipocyte (25). TNFa markedly increased cytokines IL-6 and MCP-1, which are directly regulated by NF-jB in the spiral ligament fibrocyte (26).…”

Section: Discussionmentioning

confidence: 99%

Effects of phorbol ester‐sensitive PKC (c/nPKC) activation on the production of adiponectin in 3T3‐L1 adipocytes

Ikeda

Kajita

et al. 2009

IUBMB Life

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SummaryPPARc plays a key role in adipocyte specific gene expression. In this study, we assessed the effects of phorbol ester (TPA)-sensitive PKC (c/nPKC) activation on the expression of adipocyte specific genes and inflammation related genes. Treatment with both TPA and TNFa decreased mRNA levels of PPARc, aP2, LPL and adiponectin. TNFa, but not TPA, increased IL-6 and MCP-1 mRNA levels, Next, we investigated the effects of ligands which activate c/nPKC. Insulin and angiotensin II (AII), but not high glucose, reduced PPARc, aP2 and adiponectin mRNA levels. AII-induced suppression of these genes was restored in the presence of Go6976, a specific c/nPKC inhibitor, and candesartan, an AII receptor blocker. The effect of reduced insulin was prevented by Go6976 and LY294002, a specific PI 3-kinase inhibitors. Our results indicate that activation of c/ nPKC could debilitate and/or might deteriorate insulin sensitivity in vivo, through the reduction of PPARc and adiponectin expression in adipocyte.2009 IUBMB IUBMB Life, 61(6): 644-650, 2009

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SREBP-1-independent regulation of lipogenic gene expression in adipocytes

Cited by 115 publications

References 50 publications

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

LXRα fuels fatty acid-stimulated oxygen consumption in white adipocytes

Effects of phorbol ester‐sensitive PKC (c/nPKC) activation on the production of adiponectin in 3T3‐L1 adipocytes

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