Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice

Neschen, Susanne; Morino, Katsutaro; Hammond, Linda E.; Zhang, Dongyan; Liu, Zhen Xiang; Romanelli, Anthony J.; Cline, Gary W.; Pongratz, Rebecca L.; Zhang, Xian Man; Choi, Cheol Soo; Coleman, Rosalind A.; Shulman, Gerald I.

doi:10.1016/j.cmet.2005.06.006

Cited by 231 publications

(287 citation statements)

References 63 publications

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“…A decrease in hepatic triacylglycerol pools leads to improved insulin sensitivity [10]. In the present study, HFD-feeding induced excessive lipid accumulation in liver and skeletal muscle, whereas telmisartan treatment ameliorated hepatic steatosis and muscular triacylglycerol deposition in At1a-deficient mice.…”

Section: Discussionsupporting

confidence: 50%

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Rong

Ebihara

et al. 2010

Diabetologia

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Aims/hypothesis Evidence suggests that telmisartan, an angiotensin II type 1 receptor (AT1) blocker and peroxisome proliferator-activated receptor-γ partial agonist, has beneficial actions that limit development of the metabolic syndrome and diabetes. However, the role played by AT1 inhibition in metabolic effects elicited by telmisartan remains uncertain. Here we isolated the metabolic effects of telmisartan from AT1 antagonism. Methods Male At1a (also known as Agtr1a)-deficient mice were fed a standard diet or 60% high-fat diet; those on high-fat diet were co-administered telmisartan (3 mg kg −1 day −1 by oral gavage) or vehicle for 12 weeks. Results In At1a-null mice, telmisartan prevented high-fatdiet-induced increases in (1) body weight, epididymal and inguinal white adipose tissue weight, adipocyte size and plasma leptin concentration; (2) plasma glucose and insulin concentrations and HOMA index; and (3) liver weight and triacylglycerol content. Insulin tolerance testing also indicated that telmisartan improved the high-fat-diet-induced reduction of glucose-lowering by insulin. Conclusions/interpretationThe present findings demonstrate beneficial, AT1-independent effects of the AT1 blocker telmisartan on dietary-induced obesity, insulin resistance and fatty liver in animals.

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Section: Discussionsupporting

confidence: 50%

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Rong

Ebihara

et al. 2010

Diabetologia

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“…The Gpat1 −/− mice have lower body weight, changes in the fatty acid composition of liver phospholipids [9] and resistance to the development of diet-induced fatty liver and hepatic insulin resistance [27]. Gpat1 −/− mice also show marked increases in liver acyl-CoA levels and in β-oxidation [28].…”

Section: Discussionmentioning

confidence: 99%

Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2)

Wang

Lee²,

Gong³

et al. 2007

Archives of Biochemistry and Biophysics

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Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and rate-limiting step in glycerolipid synthesis. Several mammalian GPAT activities have been recognized, including Nethylmaleimide (NEM)-sensitive isoforms in microsomes and mitochondria and an NEM-resistant form in mitochondrial outer membrane (GPAT1). We have now cloned a second mitochondrial isoform, GPAT2 from mouse testis. The open reading frame encodes a protein of 798 amino acids with a calculated mass of 88.8 kDa and 27% amino acid identity to GPAT1. Testis mRNA expression was 50-fold higher than in liver or brown adipose tissue, but the specific activity of NEM-sensitive GPAT in testis mitochondria was similar to that in liver. When Cos-7 cells were transiently transfected with GPAT2, NEM-sensitive GPAT activity increased 30%. Confocal microscopy confirmed a mitochondrial location. Incubation of GPAT2-transfected Cos-7 cells with trace (3 μM; 0.25μCi) [1-14 C]oleate for 6 h increased incorporation of [ 14 C]oleate into TAG 84%. In contrast, incorporation into phospholipid species was lower than in control cells. Although a polyclonal antibody raised against full-length GPAT1 detected an ∼89 kDa band in liver and testis from GPAT1 null mice and both 89 and 80 kDa bands in BAT from the knockout animals, the GPAT2 protein expressed in Cos-7 cells was only 80 kDa. In vitro translation showed a single product of 89 kDa. Unlike GPAT1, GPAT2 mRNA abundance in liver was not altered by fasting or refeeding. GPAT2 is likely to have a specialized function in testis.The synthesis of triacylglycerol and all glycerophospholipids begins with the acylation of glycerol-3-phosphate with long-chain fatty acyl-CoA to produce 1-acylglycerol-3-phosphate. This reaction is catalyzed by glycerol-3-phosphate acyltransferase (GPAT 1 ; EC 3.1.3.9) which exhibits the lowest specific activity of all enzymes in the glycerol-3-phosphate pathway, suggesting that it is the rate limiting step [1].Three mammalian GPAT activities have been differentiated based on their subcellular location and biochemical properties [2,3]. GPAT activity is present in microsomal and mitochondrial Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. fractions. In most tissues, 90% of the activity is attributed to a microsomal GPAT which is sensitive to inactivation by sulfhydryl reagents such as NEM. Microsomal GPAT3, prominent in adipose tissue, has been cloned [4]. Microsomal GPAT activity does not appear to be regulated in liver. In contrast, the mitochondrial isoform (GPAT1) 2 that has been purified [5] and cloned [6,7], is highly regulated by i...

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“…In contrast, there were no differences in the prevalence of insulin resistance among Asian-Indian women compared with the other ethnic groups, suggesting a potentially important protective role of estrogen in this process (16,17). There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance both in rodent models with hepatic steatosis and in patients with nonalcoholic fatty liver disease (4,(18)(19)(20)(21)(22)(23)(24)(25). Short-term high-fat feeding in rats has been shown to result in hepatic steatosis and hepatic insulin resistance, which were both reversed after treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (21).…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanism of fat-induced hepatic insulin resistance is unclear; however, recent studies in rodents suggest that intracellular increases in diacylglycerol activates protein kinase C , which activates a serine kinase cascade that in turn blocks insulin stimulation of IRS-2 tyrosine phosphorylation, an early step in insulin signaling (21,22,25).…”

Section: Discussionmentioning

confidence: 99%

Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men

Petersen¹,

Dufour

Feng³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Type 2 diabetes mellitus (T2DM) is strongly associated with obesity in most, but not all, ethnic groups, suggesting important ethnic differences in disease susceptibility. Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM and that insulin resistance is strongly associated with increases in hepatic (HTG) and͞or intramyocellular lipid content, little is known about the prevalence of insulin resistance and potential differences in intracellular lipid distribution among healthy, young, lean individuals of different ethnic groups. To examine this question, 482 young, lean, healthy, sedentary, nonsmoking Eastern Asians (n ‫؍‬ 49), Asian-Indians (n ‫؍‬ 59), Blacks (n ‫؍‬ 48), Caucasians (n ‫؍‬ 292), and Hispanics (n ‫؍‬ 34) underwent an oral glucose tolerance test to assess whole-body insulin sensitivity by an insulin sensitivity index. In addition, intramyocellular lipid and HTG contents were measured by using proton magnetic resonance spectroscopy. The prevalence of insulin resistance, defined as the lower quartile of insulin sensitivity index, was Ϸ2-to 3-fold higher in the AsianIndians compared with all other ethnic groups, and this could entirely be attributed to a 3-to 4-fold increased prevalence of insulin resistance in Asian-Indian men. This increased prevalence of insulin resistance in the Asian-Indian men was associated with an Ϸ2-fold increase in HTG content and plasma IL-6 concentrations compared with Caucasian men. These data demonstrate important ethnic and gender differences in the pathogenesis of insulin resistance in Asian-Indian men and have important therapeutic implications for treatment of T2DM and for the development of steatosis-related liver disease in this ethnic group.gender and ethnic differences ͉ hepatic steatosis ͉ insulin resistance ͉ risk of type 2 diabetes

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Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice

Cited by 231 publications

References 63 publications

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2)

Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men

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