miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling

Abstract

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoAdehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.lipid homeostasis | posttranscriptional regulation | cardiovascular disease

miRNAs link metabolic reprogramming to oncogenesis

“…The inhibition of insulin receptor substrate-1 (IRS1) by miR-126 also promotes insulin resistance [64], while miR-33a and miR-33b affect insulin signaling and glucose regulation by targeting IRS2, SIRT6 and AMPKα1 [65]. Additionally, miR-33a may regulate Pim-1, a kinase that possesses overlapping functions with Akt [66].…”

Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling

“…miR-33 affects hepatic insulin action by targeting multiple metabolic regulators, including Sirtuin 6 (SIRT6), a1 subunit of AMP-activated protein kinase (AMPKa1) and IRS2. However, whether one of these metabolic regulators alone or all of them contribute to the regulatory role of miR-33 on insulin signalling remains unclear 19 .…”

MicroRNAs in Cardiometabolic Diseases

“…(3) Finally, insulin receptor substrate 2 (Irs2), an adaptor protein that controls insulin signaling in the liver, has also been shown to be a miR-33 target, thereby affecting the signaling of a complex downstream network of proteins, including protein kinase B (also known as Akt) phosphorylation and forkhead box O1 cytoplasmic localization. (49) Collectively, these data indicate that both isoforms of miR-33 participate in the regulation of relevant pathways that impact 3 of the primary risk factors of metabolic syndrome, namely insulin resistance, low HDL, and high very-low-density lipoprotein, and suggest that anti-miR-33 therapies may be an an attractive approach for treating metabolic diseases. (3,32,51) Additional miRNAs (miR-106, miR-758, miR-26, miR-370, miR-378/378*, let-7, miR-27, miR34a, and miR-335) have been described to participate in the regulation of lipid metabolism.…”

“…(66,67) In addition to Let-7, other miRNAs, including miR-33, miR-103, miR-107, and miR29a/b, also regulate the insulin signaling pathway. (49,(68)(69)(70) Overexpression of miR-107 results in an increase in fasting glucose and insulin levels. (70) Conversely, silencing of miR-103/miR-107 enhances insulin sensitivity in the liver and in the adipose tissue.…”

“…Importantly, miR-33a and miR-33b contribute to the regulation of fatty acid metabolism by controlling the expression of carnitine O-octanyl transferase (Crot), carnitine palmitoyltransferase 1A (Cpt1a), and hydroxyacylcoenzyme A dehydrogenase/3-ketoacyl-coenzyme A thiolase/enoyl-coenzyme A hydratase (trifunctional protein) β-subunit. (49,50) In addition to the regulation of fatty acid oxidation, miR-33a and miR-33b have also been shown to control the expression of adenosine monophosphate (AMP)-activated kinase (AMPKα1) and sirtuin 6 (Sirt6), which are involved in the regulation of lipid and glucose metabolism. (49) AMPKα1 regulates key lipogenic enzymes, including HMGCR and acetyl-CoA carboxilase (ACC).…”