Inhibition of acetyl-CoA carboxylases by soraphen A prevents lipid accumulation and adipocyte differentiation in 3T3-L1 cells

Abstract

Acetyl-CoA carboxylases (ACC) 1 and 2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA and depend on biotin as a coenzyme. ACC1 localizes in the cytoplasm and produces malonyl-CoA for fatty acid (FA) synthesis. ACC2 localizes in the outer mitochondrial membrane and produces malonyl-CoA that inhibits FA import into mitochondria for subsequent oxidation. We hypothesized that ACCs are checkpoints in adipocyte differentiation and tested this hypothesis using the ACC1 and ACC2 inhibitor soraphen A (SA) in murine 3T3-L1 preadipocytes. When 3T3-L1 cells were treated with 100 nM SA for 8 days after induction of differentiation, the expression of PPARγ mRNA and FABP4 mRNA decreased by 40% and 50%, respectively, compared with solvent controls; the decrease in gene expression was accompanied by a decrease in FABP4 protein expression and associated with a decrease in lipid droplet accumulation. The rate of FA oxidation was 300% greater in SA-treated cells compared with vehicle controls. Treatment with exogenous palmitate restored PPARγ and FABP4 mRNA expression and FABP4 protein expression in SA-treated cells. In contrast, SA did not alter lipid accumulation if treatment was initiated on day eight after induction of differentiation. We conclude that loss of ACC1-dependent FA synthesis and loss of ACC2-dependent inhibition of FA oxidation prevent lipid accumulation in adipocytes and inhibit early stages of adipocyte differentiation.

Isobavachalcone from Angelica keiskei Inhibits Adipogenesis and Prevents Lipid Accumulation

“…Adiponectin acts as one of adipokines that can enhance adipocyte differentiation and lipid accumulation in mature adipocytes [ 31 ]. Acetyl-CoA carboxylase (ACC)-1 catalyzes fatty acid synthesis and contributes to lipid accumulation and adipogenesis in adipocytes [ 32 ]. Fatty acid synthase (FAS) is predominantly expressed in adipose tissue.…”

Omic Approach in Non-smoker Female with Lung Squamous Cell Carcinoma Pinpoints to Germline Susceptibility and Personalized Medicine

“…Based on the evidence that in our tumoral tissue only the mutated transcript is present, we can assume that, even if protein level is decreased, the isoform loses negative control by BRCA1 and remains active. In this case, patient could potentially benefit from a therapy with ACACA inhibitors such as miR-195 [ 28 ] or soraphen A [ 29 ] ( Fig. 3A ).…”

Cudratricusxanthone A Inhibits Lipid Accumulation and Expression of Inducible Nitric Oxide Synthase in 3T3-L1 Preadipocytes

“…Indeed, studies have demonstrated that several adipogenic transcription factors, including the family of CCAAT/enhancer-binding proteins (C/EBPs), peroxisome proliferator-activated receptors (PPARs), and signal transducer and activator of transcription (STAT) proteins play a pivotal role in preadipocyte differentiation by regulating the expression of genes related to this process [ 9 , 10 ]. It also has been shown that fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and perilipin A, which regulate lipogenesis and LDs maturation/stabilization are crucial for preadipocyte differentiation [ 11 , 12 , 13 ]. Moreover, there is evidence pointing out the positive role of numerous signaling protein kinases, such as cAMP-activated protein kinase (AMPK), protein kinase A (PKA), extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in preadipocyte differentiation [ 14 , 15 , 16 , 17 ].…”