Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but Not Obesity or Insulin Resistance in Lep/Lep Mice

Yahagi, Naoya; Shimano, Hitoshi; Hasty, Alyssa H.; Matsuzaka, Takashi; Ide, Tomohiro; Yoshikawa, Tomohiro; Amemiya-Kudo, Michiyo; Tomita, Sachiko; Okazaki, Hiroaki; Tamura, Yoshiaki; Ikoma, Yoko; Ohashi, Ken; Osuga, Jun-ichi; Harada, Kenji; Gotoda, Takanari; Nagai, Ryozo; Ishibashi, Shun; Yamada, Nobuhiro

doi:10.1074/jbc.m201584200

Cited by 338 publications

(254 citation statements)

References 37 publications

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“…Ectopic expression of a constitutively active SREBP1c surprisingly conferred lipodystrophy in mice . Other in vivo studies with a double-mutant leptin-deficient ob/ob mice and SREBP-1 2/2 mice suggested that SREBP-1 was not needed for adipose tissue expansion (Yahagi et al 2002). Overall, the data suggest that although there is in vitro evidence to show SREBP-1 is required for adipocyte differentiation, the in vivo studies consistently show that SREBP-1 expression is not critical for adipose tissue development and/or expansion.…”

Section: Srebp-1mentioning

confidence: 58%

Adipogenesis

Sarjeant

Stephens

2012

Cold Spring Harbor Perspectives in Biology

269

236

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SUMMARYAdipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.

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Section: Srebp-1mentioning

confidence: 58%

Adipogenesis

Sarjeant

Stephens

2012

Cold Spring Harbor Perspectives in Biology

269

236

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“…There is strong evidence that downregulation of SCD1 prevents or reduces the development of NAFLD, obesity and insulin resistance [29][30][31][32]. Elevated hepatic transcription of Scd1 has been reported in fat-fed mice of the 129S6 [13] and C57BL/6J [13,23] strains.…”

Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

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Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with dietinduced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to dietinduced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

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“…ob/ob mice (42). Mice lacking the VLDLR exhibit normal lipid levels and a modest decrease in epididymal adipose tissue weights and are protected from diet-induced obesity (43,44).…”

Section: Discussionmentioning

confidence: 99%

Increased Very Low Density Lipoprotein Secretion and Gonadal Fat Mass in Mice Overexpressing Liver DGAT1

Yamazaki

Sasaki

Kakinuma

et al. 2005

Journal of Biological Chemistry

132

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Acyl-CoA:diacylglycerol acyltransferases (DGATs) catalyze the last step in triglyceride (TG) synthesis. The genes for two DGAT enzymes, DGAT1 and DGAT2, have been identified. To examine the roles of liver DGAT1 and DGAT2 in TG synthesis and very low density lipoprotein (VLDL) secretion, liver DGAT1-and DGAT2-overexpressing mice were created by adenovirus-mediated gene transfection. DGAT1-overexpressing mice had markedly increased DGAT activity in the presence of the permeabilizing agent alamethicin. This suggests that DGAT1 possesses latent DGAT activity on the lumen of the endoplasmic reticulum. DGAT1-overexpressing mice showed increased VLDL secretion, resulting in increased gonadal (epididymal or parametrial) fat mass but not subcutaneous fat mass. The VLDL-mediated increase in gonadal fat mass might be due to the 4-fold greater expression of the VLDL receptor protein in gonadal fat than in subcutaneous fat. DGAT2-overexpressing mice had increased liver TG content, but VLDL secretion was not affected. These results indicate that DGAT1 but not DGAT2 has a role in VLDL synthesis and that increased plasma VLDL concentrations may promote obesity, whereas increased DGAT2 activity has a role in steatosis.Triglyceride (TG) 1 is the major energy storage form and is synthesized primarily in three tissues: liver, adipose, and small intestine. In the liver, synthesized TG is either stored in cytoplasmic droplets or secreted as very low density lipoprotein (VLDL) particles. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is a membrane-bound enzyme that catalyzes the last step in the synthesis of TG. Classified by detergent sensitivity, two types of DGATs in microsomes have been proposed: the overt type (on the cytosol) catalyzes the synthesis of TG destined for cytoplasmic droplets, and latent type (on the lumen of the endoplasmic reticulum) catalyzes the synthesis of TG for VLDL formation (1). Because it has been well established that cytosolic droplet TG cannot be incorporated en bloc into VLDL (2), the relative activities of these two functions of DGAT may have a significant impact on the level of triglyceridemia as well as on the development of steatosis.Regarding the molecular aspects of DGAT, the cDNAs of DGATs, viz. DGAT1 and DGAT2, have been recently cloned and sequenced (3, 4). DGAT1 and DGAT2 are unrelated proteins that exhibit DGAT activity. DGAT1 is expressed ubiquitously, with the highest expression levels in the small intestine (3), and the phenotypes of DGAT1-null mice have been extensively examined (5-9). DGAT1-null mice are viable, can still synthesize TG, and have normal 4-h fasted plasma TG levels (5). These mice have reduced adiposity and are resistant to diet-induced obesity through a mechanism that involves increased energy expenditure (5). The increased energy expenditure is due partly to the increased peripheral leptin sensitivity in DGAT1-deficient mice (6). DGAT2 is expressed ubiquitously, with high expression levels in the liver and white adipose tissue (WAT) (4). In contrast to DGAT1-deficient ...

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Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but Not Obesity or Insulin Resistance in Lep/Lep Mice

Cited by 338 publications

References 37 publications

Adipogenesis

Adipogenesis

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Increased Very Low Density Lipoprotein Secretion and Gonadal Fat Mass in Mice Overexpressing Liver DGAT1

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