<i>Pck1</i> Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in <i>db/db</i> Mice

Gómez-Valadés, Alícia G.; Méndez-Lucas, Andrés; Vidal‐Alabró, Anna; Blasco, Francese X.; Chillón, Miguel; Bartrons, Ramón; Bermúdez, Jordi; Perales, José C.

doi:10.2337/db07-1087

Cited by 112 publications

(100 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In obese healthy subjects, hepatic ATP content was inversely related to BMI, decreasing steadily with increasing BMI (12). Hepatic knockdown of PEPCK, one of the key gluconeogenic enzymes, ameliorated hyperglycemia and insulin resistance with increased hepatic ATP content in db/db mice (13). Overall, all of these studies revealed that a decrease in ATP content is associated with an increase in glucose production in the livers of diabetic animals and humans.…”

mentioning

confidence: 67%

“…These findings suggested that inhibition of hepatic glucose production would attenuate hyperglycemia and global insulin resistance in type 2 diabetic mice. Similarly, a previous report showed that silencing of hepatic PEPCK suppressed hepatic glucose production and improved global insulin resistance in db/db mice (13). In vitro, ATPSb overexpression increased intracellular and extracellular ATP levels in HepG2 cells and primary cultured mouse hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

Wang

Chen

et al. 2014

Diabetes

View full text Add to dashboard Cite

ATP synthase b subunit (ATPSb) had been previously shown to play an important role in controlling ATP synthesis in pancreatic b-cells. This study aimed to investigate the role of ATPSb in regulation of hepatic ATP content and glucose metabolism in diabetic mice. ATPSb expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSb elevated cellular ATP content and ameliorated hyperglycemia of streptozocininduced diabetic mice and db/db mice. ATPSb overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSb overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSb overexpression increased intracellular and extracellular ATP content, elevated the cytosolic free calcium level, and activated Akt independent of insulin. The ATPSb-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of calmodulin (CaM) completely abolished ATPSbinduced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSb-induced nuclear exclusion of forkhead box O1 in liver cells. In conclusion, a decrease in hepatic ATPSb expression in the liver, leading to the attenuation of ATP-P2 receptor-CaM-Akt pathway, may play an important role in the progression of diabetes. In past decades, diabetes became one of the major diseases threatening our health, with an estimated global prevalence of 6.4% in 2010 (1). The liver is the key tissue that releases glucose into the circulation in fasting status, and an increase in hepatic glucose production due to insulin deficiency or insulin resistance is the central event in the development and progression of type 1 or type 2 diabetes (2). Moreover, the liver is also one of the key tissues for lipid metabolism.ATP serves as an energy molecule as well as a signal molecule in many cells (3). We previously showed that leucine upregulates the ATP synthase b (ATPSb) subunit to enhance ATP synthesis and insulin secretion in rat islets, type 2 diabetic human islets, and Rattus insulin-1 (INS-1) cells. Overexpression or knockdown of ATPSb increases or reduces cellular ATP levels in INS-1 cells (4,5). Overall, these findings suggest that ATPSb plays a crucial role in controlling ATP synthesis.

show abstract

mentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

Wang

Chen

et al. 2014

Diabetes

View full text Add to dashboard Cite

show abstract

“…PCK1 catalyzes the first committed step in gluconeogenesis, and its transcription is regulated by several transcription factors involved in nutrient and hormone signals, notably glucagon and glucocorticoids, and the opposing hormone insulin (8). Silencing of hepatic PCK1 in db/db mice improves their control of glycemia, insulin sensitivity, and dyslipidemia, consistent with the function of PCK1 in gluconeogenesis (9). In addition to these gluconeogenic enzymes, the WNT-signaling effector TCF7L2 was recently identified as a critical regulator of HGP and glucose homeostasis (10).…”

Section: Introductionmentioning

confidence: 82%

“…ACSL3 and ACSL4 are essential enzymes for fatty acid metabolism (32). PCK1, the rate-limiting enzyme for gluconeogenesis, and TCF7L2, the WNT signaling effector, are crucial for glucose metabolism, especially for HGP (9,10). Lipids or other inducers of insulin resistance stimulate the activation of PKCδ, PKCθ, and GSK3β, which phosphorylate IRS proteins on Ser residues, thereby attenuating insulin signaling (3,33,34).…”

Section: Alb-mir26amentioning

confidence: 99%

MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

Fu¹,

Dong²,

Tian³

et al. 2015

J. Clin. Invest.

212

168

View full text Add to dashboard Cite

“…Because it is not possible to study this in intact cells because of the rapid metabolism of DG, we tested the ability of CETP to transfer DG in vitro. DG was incorporated into phosphatidylcholine/cholesterol liposomes and the effect of CETP on the transfer of DG to causes an equivalent decline in PCK protein ( 43 ), these data suggest that glycolysis, driven by glucose in the media, provides adequate glycerol 3-phosphate for this pathway under cell culture conditions.…”

Section: Dg As a Cetp Substratementioning

confidence: 88%

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Greene

Izem

Morton

2015

Journal of Lipid Research

View full text Add to dashboard Cite

with adipose tissue CETP mRNA levels in both man and hamster ( 6,7 ), showing the importance of this tissue in both lipid storage and the modulation of intravascular lipid metabolism.While most CETP is secreted by cells, a portion is retained ( 8-10 ). Much of the intracellular CETP pool is associated with the endoplasmic reticulum (ER), with increased concentrations near lipid droplets ( 8,11 ). Both cytoplasmic and lipid-droplet pools of CETP have been observed as well ( 11 ). Although the mechanism for CETP release into the cytoplasm is unknown, the escape of other ER luminal proteins to the cytoplasm has been reported (12)(13)(14).In addition to its role in plasma lipoprotein metabolism, multiple studies suggest that CETP has other functions. Cell-associated CETP promotes CE uptake from HDL, stimulates the cell's ability to effl ux cholesterol, and infl uences the storage of CE in cells (15)(16)(17)(18)(19). In addition to altering cellular cholesterol metabolism, both overexpression and under-expression of CETP in SW872 cells, a human cell line commonly used as an adipocyte model, reduce the capacity of these cells to store TG ( 10, 11 ). A role for CETP in adipocyte lipid storage is further supported by observations in transgenic mice. Adipose tissue-specifi c expression of human CETP in mice results in smaller adipocytes containing less TG and cholesterol, and signifi cantly reduces the expression of key lipogenic genes ( 20 ). In hypertriglyceridemic mice, CETP expression normalizes subcutaneous adipose depots and visceral adipocyte size ( 21 ). And in humans, a CETP gene variant that affects the coding sequence of CETP is associated with increased adiposity following long-term overfeeding ( 22 ).In this study, we have examined pathways involved in TG homeostasis in order to understand the metabolic Abstract We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ‫ف‬ 50% reduction in TG. The causes of this reduced TG content, investigated here, could not be attributed to changes in the differentiation status of CETP-defi cient cells, nor was there evidence of endoplasmic reticulum (ER) stress. In short-term studies, the total fl ux of oleate through the TG biosynthetic pathway was not altered in CETP-defi cient cells, although mRNA levels of some pathway enzymes were different. However, the conversion of diglyceride (DG) to TG was impaired. In longer-term studies, newly synthesized TG was not effectively transported to lipid droplets, yet this lipid did not accumulate in the ER, apparently due to elevated lipase activity in this organelle. DG, shown to be a novel CETP substrate, was also ineffi ciently transferred to lipid droplets. This may reduce TG synthesis on droplets by resident diacylglycerol acyltransferase. Overall, these data suggest that the decreased TG content of CETP-defi cient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced ...

show abstract

Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice

Cited by 112 publications

References 46 publications

Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Contact Info

Product

Resources

About