Mitochondrial uncoupling, a new element in pathogenesis of metabolic syndrome: a pilot study

Obesity and insulin resistance are the main factors in development of metabolic syndrome (MetS). In patients with MetS, there is an active accumulation of free fatty acids in the liver, which may lead to disturbances in homeostasis and metabolism of hepatocytes, thus resulting in mitochondrial dysfunction, oxidative stress, and cellular apoptosis. Mitochondrial dysfunction has been extensively studied in the context of pathogenetic features of metabolic syndrome. However, the processes of mitochondrial uncoupling remain unclear. Mitochondrial uncoupling (MU) is a process associated with a decrease in ATP synthesis and reactive oxygen species (ROS) in mitochondria. It is mediated by proteins from the UCP (uncoupling proteins) family, as well as ANT (ADP/ATP translocase). “Mild” MU is necessary for maintaining normal mitochondrial function, whereas “severe” MU may lead to mitochondrial dysfunction. Thus, the aim of the present study was to investigate the expression levels of SIRT1 V1 deacetylase, transcription factors PGC-1α, PPAR-α, PPAR-γ that stimulate lipogenesis and β-oxidation of FFAs, and expression of some genes encoding mitochondrial uncouplers ANT2 and UCP2 in the liver of patients with MetS. The study included two groups, as follows: patients with MetS (inclusion criteria: BMI > 30 kg/m², along with type 2 diabetes and/or fasting blood glucose > 5.5 mmol/L), and a control group (BMI < 30 kg/m², absence of infectious and chronic diseases). Biochemical analysis of blood parameters was conducted using the Furuno CA-180 biochemical analyzer (Furuno Electric Company, Japan) with DiaSys test systems (DiaSys Diagnostic Systems, Holzheim, Germany). The expression levels of the genes of interest in liver biopsies were assessed using quantitative RT-PCR with SYBR Green (Evrogen, Russia).

In patients with MetS, a significant increase (compared to the control group) in expression level of the PPAR-γ transcription factor was found, being associated with de novo lipogenesis in the liver, as well as increased expression of mitochondrial ANT2 uncoupler gene. Expression levels of other genes (SIRT1 V1, PGC-1α, PPAR-α, UCP2) measured in liver biopsies from the patients with MetS did not show significant changes. An increased expression of the ANT2 gene in MetS patients may be related to both compensatory protective mechanisms, e.g., activation of “mild” MU, and pathological processes resulting from “strong” MU. Further studies are needed to investigate the effects of ANT2 and UCP2 on the cellular metabolism (ATP production, ROS generation, development of oxidative stress), both directly in human liver tissue, and in cell cultures. This article presents for the first time the results concerning expression of mitochondrial uncoupler genes (ANT2, UCP2) in the liver of patients with MetS.