miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein

Abstract

miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [3H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of MTP and fatty acid synthase ( FAS) in HepG2 cells. However, dual-luciferase reporter assays indicated that MTP is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog ( PTEN) blocked the upregulation of MTP mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.

Physiological Fitness and the Pathophysiology of Chronic Lymphocytic Leukemia (CLL)

“…Interestingly, we also show that higher exosomal miR-130b levels are associated with better lipid profiles. miR-130b is a regulator of lipid homeostasis, targeting lipid oxidation and LDL receptor expression [ 87 , 88 ]. It is plausible that the higher miR-130b found in CLL-FIT patient exosomes is limiting the CLL-like cell growth utilization of lipids and promoting our observed lower growth.…”

Higher Physical Fitness Regulates In Vitro Tumor Cell Growth in Older Adults with Treatment Naïve Chronic Lymphocytic Leukemia (CLL)

“…Interestingly, we show here that higher exosomal miR-130b expression is associated with better lipid profiles suggesting that miR-130b has a role in CLL lipid homeostasis. Indeed, miR-130b is a potential regulator of lipid homeostasis, targeting lipid oxidation and LDL receptor expression [89, 90]. That said, dyslipidemia and hypercholesterolemia also likely have complex roles in the pathogenesis of CLL, but these are not fully understood [91, 92].…”

CRISPR/Cas9-Mediated Knockout of miR-130b Affects Mono- and Polyunsaturated Fatty Acid Content via PPARG-PGC1α Axis in Goat Mammary Epithelial Cells

“…A previous study showed that bta-miR-130a/b suppressed cellular TAG and lipid droplet accumulation, by directly targeting PPARG and CYP2U1 in bovine preadipocytes [ 17 ]. miR-130b promoted hepatic VLDL assembly and secretion by increasing MTP expression and TAG mobilization in immortalized human hepatocytes [ 18 ]. In GMEC, miR-130b impaired adipogenesis and targeted both the coding sequence and 3′-untranslated regions (UTR) of PGC1α [ 19 ].…”