MiR‐22 modulates the expression of lipogenesis‐related genes and promotes hepatic steatosis in vitro

Abstract

Non-alcoholic fatty liver disease (NAFLD) is highly correlated with obesity, and lifestyle changes to reduce weight remain the main therapeutic approach. The non-coding RNA miR-22 has previously been reported to be highly abundant in the sera of NAFLD patients. In addition, miR-22 directly targets peroxisome proliferative activated receptor, Pgc-1α, PPARα, and Sirt1, which are important factors involved in fatty acid metabolism. Given that miR-22 directly targets genes involved in the control of metabolism and obesity, we investigated whether miR-22 contributes to metabolic alterations induced by obesity. We observed increased expression of miR-22, decreased expression of Sirt1, and alterations in the expression of adipogenesis-related genes in a mouse model of obesity and a human hepatocyte cell line. We identified that miR-22 and the 3'-untranslated region (UTR) of Sirt1 are complementary. Mutation of the complementary fragment abolishes the ability of miR-22 to regulate the Sirt1 gene. Furthermore, treatment of hepatic steatosis cells with miR-22 mimics or inhibitors showed that miR-22 can promote hepatic steatosis, and miR-22 inhibitors effectively reduced triglyceride levels without affecting cell activity. Finally, we validated that miR-22 has similar effects on downstream lipid metabolism-related genes. Our data reveal the pathways and mechanisms through which miR-22 regulates lipid metabolism, and suggest that miR-22 inhibitors may have potential as candidate drugs for NAFLD and obesity.

Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review

“…The transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α, which regulates the expression of genes involved in energy metabolism, is a key target of Nox. 122 PGC-1α is directly regulated by SIRT1 through phosphorylation and deacetylation; 123 Meanwhile, SIRT1 is upregulated by icariin, 93 which stimulates the transcriptional activity of PGC-1α in neuron metabolism and mitigates mitochondrial dysfunction by inducing the upregulation of SIRT1 deacetylase. 116 Additionally, icariin reduced ROS levels and brain edema following middle cerebral artery occlusion by inhibiting lactate dehydrogenase release, thereby decreasing the level of malondialdehyde and enhancing superoxide dismutase activity.…”

PPARα in the Epigenetic Driver Seat of NAFLD: New Therapeutic Opportunities for Epigenetic Drugs?

“…Some of these altered miRNAs target nuclear receptors, including PPARα [ 65 ]. For example, miR-200, miR-20b, miR181-a, miR-30a-3p, miR519d, miR-21 and miR-22 are elevated in NAFLD and directly target PPARα mRNA [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. The working mechanism of these miRNAs leading to the aggravation of NAFLD is approximately the same.…”

“…They all bind to the 3′UTR of PPARα mRNA resulting in PPARα mRNA degradation, decreased protein expression and disturbed lipid metabolism, leading to the aggravation of an NAFLD phenotype. Moreover, the induced expression of specific miRNAs (miR-20b, miR181-a, miR-30a-3p and miR-22) in FFA-treated hepatocytes increased the intracellular lipid content upon reduction in PPARα mRNA levels and decreased protein expression [ 66 , 67 , 69 , 70 ]. Moreover, even in colorectal cancer-derived liver metastasis, deregulated PPAR targeting miRNAs have been observed [ 73 ].…”

Assessment of immunostimulatory responses to the antimiR-22 oligonucleotide compound RES-010 in human peripheral blood mononuclear cells

“…MicroRNAs (miRNAs) are short endogenous non-coding RNAs, about ∼22 nucleotides in length, that function as post-transcriptional regulators of gene expression by repressing protein translation and promoting mRNA cleavage ( Bartel, 2009 ). MiR-22 has been identified as a key regulator of lipid and metabolic homeostasis ( Kaur et al, 2011 ; Wang et al, 2020 ), which functions by orchestrating multiple gene regulatory networks including lipid biosynthesis ( Koufaris et al, 2016 ; Yang et al, 2021 ; Lopez-Riera et al, 2017 ; Yang et al, 2012 ; Zou et al, 2019 ), mitochondria biogenesis and brown adipose tissue differentiation ( Fenzl and Kiefer, 2014 ; Lou et al, 2021 ). Furthermore, the levels of miR-22 are increased during human adipocyte differentiation and in white adipose tissue (WAT) from obese human subjects compared to WAT obtain from lean subjects.…”