Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance

Beaven, Simon W.; Matveyenko, Aleksey V.; Wroblewski, Kevin; Chao, Lily C.; Wilpitz, Damien C.; Hsu, Tu Wen; Lentz, Jacob; Drew, Brian G.; Hevener, Andrea L.; Tontonoz, Peter

doi:10.1016/j.cmet.2013.04.021

Cited by 131 publications

(128 citation statements)

References 72 publications

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“…It is not unprecedented for WAT DNL to be increased when liver DNL is low. Independent models of altered lipid metabolism have demonstrated a relationship between liver DNL and WAT DNL, with reduced hepatic DNL accompanied by upregulated adipose DNL, likely as a compensatory response ( 34,35 ).…”

Section: Discussionmentioning

confidence: 99%

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

Burhans

Flowers

Harrington

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.orgRecently, the prevalence of overweight among all adults in the US was estimated to be nearly 70% ( 1 ), and has increased more than 2-fold since 1980 ( 2 ). With increased adiposity, lipids accumulate ectopically and are associated with increased risk for detrimental metabolic conditions such as nonalcoholic fatty liver disease, insulin resistance, and hypertriglyceridemia ( 3-5 ). The balance of lipid storage between liver and adipose depots may play an important role in disease vulnerability. Fat may be synthesized from dietary carbohydrates via de novo lipogenesis (DNL), or sequestered from circulating lipids. The contribution of hepatic and adipose tissue DNL-derived fat to wholebody adiposity is controversial. While it is considered to be quantitatively minimal by some ( 6, 7 ), others have demonstrated that DNL-derived lipids can negatively impact metabolic health and contribute to hepatic steatosis and visceral adiposity in humans ( 8-10 ). Of particular importance in the context of whole-body metabolic homeostasis, recent evidence suggests that de novo synthesized fatty acids and lipids serve important signaling and regulatory roles in cellular and systemic metabolism ( 7,11 ).MUFAs are major components of tissue lipids such as TGs, cholesteryl esters (CEs), and GPs , and high levels of MUFAs are inversely associated with metabolic health. The stearoyl-CoA desaturase (SCD) family of enzymes catalyzes the synthesis of MUFAs by insertion of a cis double bond at the ⌬ 9 position of saturated fatty acids. DK062388, ADA 7-13-BS-118, and USDA Hatch W2005 (to J.M.N.), and NIH Grant RO1 AG037000 (to R.M.A.) Abbreviations: ASM, acid soluble metabolite; CE, cholesteryl ester; DNL, de novo lipogenesis; GKO, stearoyl-CoA desaturase 1 global knockout; GLC, gas liquid chromatography; GLS5, global knockout liver-specifi c stearoyl-CoA desaturase 5 transgenic; GLS3, global knockout liver-specifi c stearoyl-CoA desaturase 3 transgenic; LD, lipogenic diet; LKO, stearoyl-CoA desaturase 1 liver knockout; SCD, stearoyl-CoA desaturase; WAT, white adipose tissue .1 To whom correspondence should be addressed. e-mail: jmntambi@wisc.edu The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three fi gures and nine tables. METHODS Animals and dietsTwo liver transgenic mouse lines were generated by cloning either the human SCD5 cDNA sequence or the mouse SCD3 cDNA sequence into the pLiv.LE6 vector construct (a kind gift from John Taylor, Gladstone Institute) ( 20 ). Mice were backcrossed at least seven generations with C57BL/6 mice to generate SCD5Tg+ and SCD3Tg+ mice. SCD5Tg+ and SCD3Tg+ mice were then crossed with SCD1 GKO mice (in C57BL/6 background) to generate compound heterozygous mice, SCD1+/ Ϫ carrying one copy of the SCD5 or SCD3 transgene. These compound heterozygous mice were then bred with female SCD1+/ Ϫ or male SCD1 Ϫ / Ϫ mice to generate SCD5Tg+;SCD1 Ϫ / Ϫ (GLS5) and SCD3Tg+;SCD1 Ϫ / Ϫ (GLS3) mice.Mice wer...

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Section: Discussionmentioning

confidence: 99%

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

Burhans

Flowers

Harrington

et al. 2015

Journal of Lipid Research

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“…Recently, studies on animal models and cell lines clearly show a cross talk between PPARγ and LXR in the regulation of adipocyte metabolism (8,72,73). This new finding could explain some discrepancies observed in the literature between LXR knockout studies and LXR activation studies in mouse models.…”

Section: Lxr In Lipolysismentioning

confidence: 71%

“…All together, these data suggest LXR as a valuable target in the treatment of obesity. Recent work on LXRα/β KO mice on an ob/ob background (LOKO) has shown that LOKO mice are more insulin sensitive and show reduced liver TG content but induced adipose depots compared to the control ob/ob mice (8). In LOKO mice, PPARγ signaling pathway, a hallmark of improved insulin sensitivity, in adipose tissue was highly induced.…”

Section: Lxr In Lipolysismentioning

confidence: 99%

“…Liver X receptors (LXR)α (NR1H3) and β (NR1H2) are two members of the nuclear receptor (NR) family involved in multiple metabolic pathways including energy expenditure (1-3), insulin signaling (4)(5)(6), and metabolism of glucose, lipid (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and cholesterol (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). They play key roles in atherosclerosis (28,29), inflammation (7,30), and CNS development (31,32).…”

Section: Introductionmentioning

confidence: 99%

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Liver X receptors as regulators of metabolism

Korach-André

Gustafsson²

2015

Biomolecular Concepts

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Abstract:The liver X receptors (LXR) are crucial regulators of metabolism. After ligand binding, they regulate gene transcription and thereby mediate changes in metabolic pathways. Modulation of LXR and their downstream targets has appeared to be a promising treatment for metabolic diseases especially atherosclerosis and cholesterol metabolism. However, the complexity of LXR action in various metabolic tissues and the liver side effect of LXR activation have slowed down the interest for LXR drugs. In this review, we summarized the role of LXR in the main metabolically active tissues with a special focus on obesity and associated diseases in mammals. We will also discuss the dual interplay between the two LXR isoforms suggesting that they may collaborate to establish a fine and efficient system for the maintenance of metabolism homeostasis.

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“…Accordingly, several ONRs have been examined for their roles in insulin resistance and type 2 diabetes. For example, the liver X receptor (now an adopted ONR due to the identification of a ligand) global knockout mouse model shows improved muscle, hepatic and adipose tissue insulin sensitivity [5]. Moreover, the PPARs (another class of adopted ONRs) have received much attention as potential pharmacological targets for combating obesity and diabetes due to their important role in cell metabolism (specifically lipid metabolism) regulation [6] and amelioration of insulin resistance in skeletal muscle and liver [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Analysis of Orphan Nuclear Receptors in Insulin-Resistant C2C12 Skeletal Muscle Cells

Chew¹,

Gawned²

2015

J Diabetes Metab

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Orphan nuclear receptors (ONR) are members of the nuclear receptor (NR) super family of transcription factors that have been known to play a major role in lipid and glucose metabolism in skeletal muscle. Recently, pharmacological evidence supports the view that stimulation of NR alleviates Type 2 Diabetes (T2D). However the ligands and physiological functions of ONRs still remain unknown. To date, no systematic studies have been carried out to screen for ONRs expressed in insulin resistant skeletal muscle cells. Therefore, in this study, we have established a model for insulin resistance (IR) by treating C2C12 skeletal muscle cells with insulin (10nM) for 48 hours. Western Blot analysis of phosphorylated AKT confirmed IR. By quantitative PCR, we identified that a number of the ONRs respond significantly during the progression of cellular insulin resistance which included Couptf1, Coup-tf2, Pparβ, NR4As, Reverbα, and Rorα, some of which have been associated with fatty acid oxidation regulation and glucose homeostasis and therefore could play a role in the aetiology of this disorder. Highlighted were observed increased mRNA expression levels of other ONRs in insulin resistant C2C12 skeletal muscle cells, indicated that these ONRs could potentially play a pivotal regulatory role of insulin secretion in lipid metabolism. Taken together, this study has successfully contributed to the analysis of ONR in IR, and has filled in an important void in the study and treatment of T2D.

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Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance

Cited by 131 publications

References 72 publications

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

Liver X receptors as regulators of metabolism

Quantitative Analysis of Orphan Nuclear Receptors in Insulin-Resistant C2C12 Skeletal Muscle Cells

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