Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

Abstract

1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1α/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1α or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1α/Stra13 (DEC1) pathway.

Hepatic proteomic analysis revealed altered metabolic pathways in insulin resistant Akt1 +/− /Akt2 −/− mice

“…It was reported recently that the expression of carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) decreased in type 2 diabetic mice [56]. Another study showed that carboxylesterase expression and activity were inhibited by lipopolysaccharide or interleukin-6 under hyperglycemic conditions in primary mouse hepatocytes [57].…”

Circadian rhythmicity: A functional connection between differentiated embryonic chondrocyte-1 (DEC1) and small heterodimer partner (SHP)

“…These observations suggest that SHP positively regulates glucose homeostasis. In contrast, high glucose and high insulin significantly induced DEC1 [48, 49]. The induction of DEC1 was inhibited by LY294002, a strong inhibitor of phosphoinositide 3-kinases.…”

Enhanced Platelet Response to Clopidogrel in Zucker Diabetic Fatty Rats due to Impaired Clopidogrel Inactivation by Carboxylesterase 1 and Increased Exposure to Active Metabolite

“…In humans, CES1 activity was higher in white adipose tissue of obese and T2DM patients (Dominguez et al, 2014), whereas hepatic CES1 expression was increased in diabetic ob/ob and db/db mice (Xu et al, 2014). However, Chen et al (2015) found that the expression and activity of CES1 were lower in the small intestine and liver of streptozotocin-induced diabetic mice than in control mice. Similarly, in the present study, we found that the protein level and catalytic activity of CES1 and the level of Ces1e mRNA in the livers of ZDF rats were significantly lower than in control rats.…”

“…Diabetes is a risk factor for coronary artery disease, cerebrovascular disease, and severe peripheral vascular disease (Luscher et al, 2003), all of which can benefit from the use of Clop. Accumulated evidence points to altered expression and activity of hepatic CYPs and CES in diabetes (Kim and Novak, 2007;Dominguez et al, 2014;Xu et al, 2014;Chen et al, 2015), strongly implicating an interaction between the disease and Clop metabolism. In fact, clinical studies have shown that diabetic patients tend to have a poor response to Clop (Yusuf et al, 2001;Angiolillo et al, 2005Angiolillo et al, , 2007Brandt et al, 2007;Wiviott et al, 2007) characterized by a lower plasma level of clop-AM and no change in platelet P2Y 12 receptor function (Erlinge et al, 2008;Angiolillo et al, 2014).…”