MicroRNAs in Metabolic Syndrome
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Metabolic syndrome (MetS) corresponds to a cluster of several risk factors that increase the risk of other health problems, such as cardiovascular disease and diabetes. The combinatorial nature of MetS makes its etiology complex as it is determined by the interplay of both genetic and environmental factors like nutrition or physical activity. Accordingly, intricate regulatory networks have evolved to respond to changes in environmental conditions and physiological stress. In the search for key molecular pathways that could elucidate the complex physiopathology of MetS, as well as serve as therapeutic tools, microRNAs (miRNAs) have emerged as attractive molecules, given their role as important components of complex gene regulatory networks. MiRNAs typically control the expression of their target genes by imperfect base pairing to the 3′ untranslated regions (3′UTR) of their messenger RNAs (mRNAs) targets. Currently, several aspects of the miRNA biogenic process are known in detail, as well as the translational repression mechanisms exerted by miRNAs on their target mRNAs. The number of studies associating miRNAs with the metabolic risk factors of MetS is increasing; however, few studies directly relate miRNAs to a well-defined model of MetS. There is no doubt that miRNAs play an important role in the development of individual components of MetS; however, our understanding of their function during the different combinatorial modalities of MetS is poor. In this chapter, we review several of the studies investigating the relationship between miRNA dysfunction and MetS. We discuss the role of nutrition and genetic in the modulation of miRNAs activities and how our dietary behavior can have profound consequences in the metabolic health of our progeny.
KeywordsMetabolic syndrome High-fat diet Maternal obesity Paternal obesity Diabetes Nutrition Metabolism MicroRNAs Epigenetics Transgenerational inheritance Genetic burden
List of Abbreviations
3′ untranslated region
- messenger RNAs
miRNA-induced silencing complex
miRNA recognition element
Nonalcoholic fatty liver disease
Single nucleotide polymorphisms
Type-2 diabetes mellitus
Metabolic syndrome (MetS), also known as “plurimetabolic syndrome,” “syndrome X,” “deadly quartet,” “insulin resistance syndrome,” and “dysmetabolic syndrome,” corresponds to a cluster of risk factors that increases the risk of other health problems, such as cardiovascular disease and diabetes. The variety of names that the syndrome has been given throughout its history is a reflection of the difficulties that physicians and scientists have had in agreeing on a unique definition, diagnosis and treatment. Currently, individuals with three out of five metabolic conditions – abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein (HDL), hypertension, and impaired fasting glucose – are diagnosed with MetS, and their chances of suffering a stroke or developing diabetes are significantly higher than those if only one of these risk factors is present (Alberti et al. 2009; Grundy et al. 2005). Additionally, several other metabolic disorders, such as liver fat accumulation, have been associated with MetS (Boyraz et al. 2014). The combinatorial nature of the syndrome makes its etiology complex as it is determined by the interplay of both genetic and environmental factors (Miyamoto et al. 2009; Ye et al. 2013).
In the search for key molecular pathways that could elucidate the complex physiopathology of MetS, as well as serve as therapeutic tools, microRNAs (miRNAs) have emerged as attractive molecules, given their role as important components of complex gene regulatory networks (Yousef et al. 2014). miRNAs are small endogenous noncoding RNAs; in their mature form (approximately 22 nt), they are loaded onto a protein complex called the miRNA-induced silencing complex (miRISC) and direct the sequence-specific binding of the complex to target messenger RNAs (mRNAs), repressing their translation (Bartel 2009). Because the miRNA–mRNA binding site is very short (8–14 nt), each miRNA has the potential to regulate many target genes, and one gene may be targeted by several miRNAs (Bartel 2009). Additionally, miRNAs have different functional modalities that provide another layer of complexity to the miRNA-mediated effects (Codocedo et al. 2016). For example, the short recognition elements (miRNA recognition element, MRE) may occur in many transcripts that participate in the same pathway, indicating that a single miRNA could affect a whole pathway. Several reports have shown that a change in a single miRNA-target interaction can simultaneously affect multiple other miRNA-target interactions and modify physiological phenotypes (Hanin et al. 2014). Furthermore, the biogenesis of miRNAs is a complex multistep process that is modulated by several environmental factors, including nutrition, to generate homeostatic responses (Codocedo and Inestrosa 2016). The complex biology of miRNAs is hence compatible with a key role in metabolic functions. Thus, analysis of their deregulation in MetS patients and animal models could help to develop better therapeutic strategies to improve the quality of life of the increasing population of MetS patients.
The number of studies associating miRNAs with the metabolic risk factors of MetS is increasing; however, few studies directly relate miRNAs to a well-defined model of MetS. In this chapter, we review several of the studies investigating the relationship between miRNA dysfunction and MetS. We consider evidence that describes the role of the environment in the form of nutrition, as well as the genetic component in the form of mutation in metabolic miRNAs as well as their targets. Finally, we discuss the interaction between both components and their consequences in the offspring of progenitors affected by MetS, in a mechanism that could explain the epidemic increase in obesity, diabetes, and MetS.
Nutritional Modulation of miRNAs and Their Role in MetS
The mechanism by which diet regulates miRNA expression and, in consequence, contributes to the genesis of metabolic conditions is not fully understood. In both animal models and patients with MetS, altered expression levels of different miRNAs have been observed as a consequence of changes at different stages of biogenetic processes, including transcription, processing, and miRISC function. One of the best-studied transcription factors that regulate miRNA expression is the p53 tumor suppressor protein, which regulates the expression of stress-response genes, including the miR-34 family. Interestingly, the p53/miR-34 axis has been shown to be upregulated in islets of diabetic db/db mice and the beta-cell line MIN6B1. Treatment with fatty acids, such as palmitate, which is a predisposing factor for T2DM, also upregulates p53/miR-34 in the pancreatic islets of diabetic mice (Lovis et al. 2008). p53 has also been shown to participate in other clusters of MetS-related conditions, such as nonalcoholic fatty liver disease (NAFLD) (Castro et al. 2013). Additionally, p53 not only regulates miRNAs at the transcriptional level but also regulates the processing/maturation of additional miRNAs, including miR-16-1, miR-143, and miR-145. p53 was shown to interact with the DEAD-box RNA helicase p68 (also known as DDX5) and enhance its interaction with the DROSHA complex, thereby promoting miRNA maturation (Suzuki et al. 2009). This mechanism of p53 was described in the context of cancer development; however, its role in the induction of MetS has not yet been studied. Interestingly, several reports have shown that either lack of nutrients and excessive or deregulated signaling through the nutrient-sensing pathways can activate a p53 response (Hanin et al. 2014; Lee et al. 2007, 2009; Okoshi et al. 2008). Other studies have demonstrated that increased glucose metabolism stimulated by the expression of the glucose transporter GLUT1 or hexokinase also suppressed p53 activity (Zhao et al. 2008).
More recently, how nutritional factors induce changes in miRNAs through epigenetic DNA modifications and their role in the development of metabolic risk factors have been investigated (Yan et al. 2016). One of the major epigenetic mechanisms is DNA methylation, which is important in insulin sensitivity (Ma et al. 2013), obesity (Ali et al. 2016; Kühnen et al. 2016), and cardiovascular diseases (Rask-Andersen et al. 2016). DNA methylation leads to a decrease in gene transcription by inhibiting the binding of transcription factors to gene promoters (Kirchner et al. 2013; Nguyen et al. 2001). Recently, a reduction in miR-9 levels was found in the livers of HFD mice and ob/ob mice. Interestingly, this report described a concomitant increase in DNA methylation at the miR-9 promoter, which could be due to enhanced accumulation of DNA methyltransferase 1 (DNMT1) at the miR-9-3 promoter (Yan et al. 2016). miR-9 has been associated with the development of T2DM based on evidence showing that miR-9 plays an important role in the regulation of in vitro and in vivo insulin secretion via regulation of targets such as SIRT1 (Ramachandran et al. 2011) or Onecut-2 (Oc2) (Plaisance et al. 2006). The identification of new targets of miR-9, such as FOXO1, in the livers of obese mice has uncovered new biological roles associated with T2DM, including gluconeogenesis and insulin resistance (Yan et al. 2016). Despite the important advances made in this field, several questions are still unsolved. For example, it is not clear which signaling pathways the cells use to integrate specific nutritional manipulations and induce changes in miRNA expression that contribute to the development of MetS. Additionally, most of the preclinical studies did not determine whether the animals developed comorbidities suggestive of MetS at the end of the feeding protocol. Moreover, in several studies, the miRNA evaluation was performed when the animals reached a final metabolic state, such as T2DM, NAFLD, or a cardiac condition. As MetS is considered an early stage in the metabolic deterioration (i.e., prediabetic), the altered miRNAs observed in these animals have to be evaluated with caution because they could represent changes related to the advanced stage of MetS or not be related at all.
Genetics of miRNAs and Their Role in MetS
Parental Inheritance of MetS and the Role of miRNAs
In modern societies, the consumption of highly caloric foods and sedentary lifestyle has increased the rates of obesity, T2DM, and MetS at a pace that reaches pandemic levels. Additionally, individual genetic predispositions (or resistance) could worsen (or alleviate) the pathological outcome of a dietary challenge. Different molecules and biological pathways have been proposed as the mechanism by which organisms integrate the environmental signals and stressors that result in the development of the metabolic clusters that compose the MetS. In that sense, miRNAs have emerged as attractive molecules, given their role as important components of complex gene regulatory networks. miRNAs play a critical role in the development of individual components of MetS; however, our understanding of their function during the different combinatorial modalities of MetS is poor. More detailed metabolic profiles of the animals used for metabolic manipulations are needed to determine whether the miRNA alterations occur in a context of MetS.
Finally, the study of inter- and transgenerational inheritance has shown that our dietary sins are passed on to our children in the form of epigenetic modifications, such as DNA methylation, chromatin modification, and miRNAs. Biological examples have been documented of phenotypic plasticity emerging in relatively fast time-scales and of frequencies that are orders of magnitude higher than can be explained by natural selection of genetics variants. The hypothesis that our nutritional experiences are coded in our epigenome could help to explain the exponential increase in obesity, T2DM, and MetS observed in the modern world.
In USA, nearly 35% of all adults and 50% of those aged 60 years or older were estimated to have the metabolic syndrome.
Each miRNA potentially regulates hundreds of target gene products, and it is suggested that the entire protein coding genome is regulated by miRNAs.
Recently, a rapidly growing number of miRNAs have been implicated in regulation of genes and proteins involved in the control and maintenance of metabolic homeostasis including cholesterol and lipid homeostasis, insulin signaling and glucose homeostasis, as well as cardiometabolic disorders such as obesity, NAFLD, insulin resistance, T2DM, and coronary artery disease.
Environmental factors like nutrition could regulate the expression of miRNAs through different mechanisms including the modulation of their transcription, processing or assembling in their functional complex, miRISC.
Change in metabolic miRNAs could be passed to next generations through intergenerational and transgenerational inheritance which may exacerbate the epidemic of MetS.
Dictionary of Terms
Pri- and pre-miRNA – MicroRNAs are transcribed via Pol II into primary-microRNAs (pri-miRNA), which are then cleaved in the nucleus by the enzyme DROSHA. The hairpin structure formed by this cleavage is referred to as a pre-miRNAs (Fig. 1).
MicroRNA recognition element (MRE) – Correspond to a short sequence in the 3′UTR of the mRNA target that bind to the seed sequence in their cognate miRNA through imperfect RNA-RNA base pairing that involves not only the Watson-Crick A:U and G:C pairs but also the G:U pair.
miRNA-induced silencing complex (miRISC) – A ribonucleoprotein complex loaded with a specific miRNA that mediate translational repression of their mRNA target. The core proteins of the miRISC are Dicer, a class III RNase III, Argonaute (which bind to different classes of small noncoding RNAs, including microRNAs) and TAR RNA binding protein, a double-stranded RNA binding protein.
High-fat diet (HFD) – A diet-induced obesity model, that closely mimics the increasingly availability of the high-fat/high-density foods in modern society, which are main contributors to the obesity trend in human.
Transgenerational Inheritance – Correspond to the transmittance of epigenetic modifications (excluding DNA sequence changes) from one generation of an organism to the next one that affects the traits of offspring. In their stricter sense, the transgenerational inheritance occurs when a generation presents the trait and the epigenetic modification but never was exposed to the environmental challenges that induce such changes in their parents.
In modern societies, the consumption of highly caloric foods and sedentary lifestyle has increased the rates of obesity, T2DM, and MetS at a pace that reaches pandemic levels.
Metabolic syndrome corresponds to a cluster of several risk factors that increases the risk of other health problems, such as cardiovascular disease and diabetes.
miRNAs are small endogenous noncoding RNAs that typically control the expression of their target genes by imperfect base pairing to the 3′UTR of their messenger RNAs targets.
Nutritional components affect the expression and activity of endogenous miRNAs through different mechanisms, including modulation of critical enzymes of the miRNA biogenetic pathway or modulation of components of the miRISC.
Different individuals and populations possess a genetic burden, including mutations in miRNA genes, that made them either resistant or vulnerable to the development of MetS.
Mutations within the miRNA genes could potentially affect the processing or target selection of miRNAs by different means, including their transcription; pri-miRNA and pre-miRNA processing; and via miRNA–mRNA interactions.
Genetic polymorphisms that reside in the 3′UTR of miRNA target genes, which can eliminate an existing binding site, create an erroneous binding site, or affect binding affinity.
Epigenetic mechanisms may exacerbate the epidemic of MetS by first contributing to the development of MetS risk factors and then passing modifications on to the subsequent generation via parental inheritance.
The underlying mechanism by which environment shapes the organism is through epigenetic modifications, which involve DNA methylation, posttranslational histone modifications, and changes in miRNA levels.
The analysis of miRNA deregulation in MetS patients and animal models could help to develop better therapeutic strategies to improve the quality of life of the increasing population of MetS patients.
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