Carboxylesterase 1 Gene Duplication and mRNA Expression in Adipose Tissue Are Linked to Obesity and Metabolic Function

Abstract

Context and AimsCarboxylesterase 1 (CES1) appears to play an important role in the control of the metabolism of triglycerides and cholesterol in adipocytes and other cell types including hepatocytes. Therefore, it is relevant to gain insights into the genetic versus non-genetic mechanisms involved in the control of CES1 mRNA expression. Here, we investigated CES1 mRNA expression level in adipose tissue and its association with measures of adiposity and metabolic function in a population of elderly twins. Furthermore, the heritability of CES1 mRNA expression level in adipose tissue and the effect of CES1 gene duplication were assessed.MethodologyA total of 295 monozygotic and dizygotic twin subjects (62–83 years) with (n = 48) or without (n = 247) type 2 diabetes mellitus were enrolled in the study. They were subjected to a standard oral glucose tolerance test and excision of abdominal subcutaneous fat biopsies during the fasting state. Levels of CES1 mRNA and copy number of the gene were assessed by quantitative PCR.Results CES1 mRNA expression level in adipose tissue was positively associated with body-mass index (P<0.001), homeostasis model assessment-insulin resistance (P = 0.003) and level of fasting glucose (P = 0.002), insulin (P = 0.006), and triglycerides (P = 0.003). The heritability for the expression of CES1 mRNA in adipose tissue was high. CES1 gene duplication was positively associated with insulin sensitivity (P = 0.05) as well as glucose tolerance (P = 0.03) and negatively associated with homeostasis model assessment-insulin resistance (P = 0.02). Duplication of CES1 was not linked to mRNA level of this gene (P = 0.63).ConclusionCES1 mRNA in adipose tissue appears to be under strong genetic control and was associated with measures of metabolic function raising the possibility of a potential role of this enzyme in the development of type 2 diabetes mellitus. Further studies are needed to understand the potential effect of CES1 gene duplication on adipocyte and whole-body metabolic functions.

Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules

“…In recent years, the morbidity of metabolic diseases has continued to grow, and hyperlipidemia is one common type of metabolic disease. To date, only a handful of studies have been conducted regarding the relationship between metabolic syndrome and CES, and these have mainly focused on the CES-mediated hydrolysis of the endogenous lipids [35][36][37]. Even so, there are some reports about the influence of a HFD on the hydrolysis of drugs that contain ester bonds and that are catalyzed by CES.…”

“…For example, an HFD did not alter most mRNA expression levels of most lipase/ esterases in the adipose tissue [35]. Importantly, the CES1 mRNA expression levels in the adipose tissues were positively associated with the body-mass index and the TG levels [36]. An HFD appeared to induce a slight upregulation of CES in the plasma [37].…”

Association Between Copy Number Variation Losses and Alcohol Dependence Across African American and European American Ethnic Groups

“…It is involved in xenobiotic (Redinbo et al, 2003), fatty acid and cholesterol (Jernås et al, 2009) metabolisms. Mutations within the 16q12.2 cytoband or the CES1 gene have been connected with cerebral cortical malformations (Piao et al, 2002), amyotrophic lateral sclerosis (Abalkhail et al, 2003), anti-tuberculosis drug-induced hepatotoxicity (Wu et al, 2012) and obesity (Friedrichsen et al, 2013). Even though we do not know the correspondent pathway, the association of this CNVR with AD is promising given the fact that the spanned genes have a direct relationship with liver and hydrolysis functions involving the alcohol compound.…”

The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect

“…CES1 hydrolyzes the aforementioned substrates by releasing an alcohol substituent to form a fatty acylenzyme intermediate that reacts with water and releases an acyl groupcontaining molecule. CES1 is involved in the deesterification and transesterification of lipids as it has cholesterol transferase activity, which enables the formation of cholesteryl esters in the pres ence of free cholesterol [22]. It has also been reported that regulation of macrophage reverse cholesterol transport (mRCT) is facilitated by hydrolytic CES metabolism of chol esteryl esters found within cytoplasmic lipid droplets [23].…”

“…CES1A3 results from gene duplication and has been shown to increase the production of CES1 and, hence, CES1 activity [22]. It has been reported that the "daughter" copy of the gene is transcribed at a lower level than the "mother" copy and the transcripts of CES1A3, and its func tional counterpart can compete for the same transacting factors involved in mRNA degradation [22]. Thus, the high levels of transcripts generated from CES1A3 may protect the transcript of the functional homolog from degradation and thereby increase its translation.…”