In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis

Abstract

As adipose tissue is the major cholesterol storage organ and most of the intracellular cholesterol is distributed to lipid droplets (LDs), cholesterol homeostasis may have a role in the regulation of adipocyte size and function. ACATs catalyze the formation of cholesteryl ester (CE) from free cholesterol to modulate the cholesterol balance. Despite the well-documented role of ACATs in hypercholesterolemia, their role in LD development during adipogenesis remains elusive. Here, we identify ACATs as regulators of de novo lipogenesis and LD formation in murine 3T3-L1 adipocytes. Pharmacological inhibition of ACAT activity suppressed intracellular cholesterol and CE levels, and reduced expression of genes involved in cholesterol uptake and efflux. ACAT inhibition resulted in decreased de novo lipogenesis, as demonstrated by reduced maturation of SREBP1 and SREBP1-downstream lipogenic gene expression. Consistent with this observation, knockdown of either isoform reduced total adipocyte lipid content by approximately 40%. These results demonstrate that ACATs are required for storage ability of lipids and cholesterol in adipocytes.

Lipid Droplets in Neurodegenerative Disorders

“…They are comprised of acyl-glycerols that are synthesized through the action of diacylglycerol transferases (DGATs), which convert acyl-CoA-bound fatty acids, and diacylglycerols (DAGs) into the TAGs that fill the LD core (Harris et al, 2011). Cholesterol acyltransferases synthesize CEs which are also incorporated into the core of nascent LDs (Zhu et al, 2018). Once separated from the ER membrane, LDs may continue to grow via LD fusion and further TAG incorporation.…”

C. elegansACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF‐1 signaling

“…28 We previously demonstrated that both pharmacological inhibition of ACAT activity and ACAT knockdown resulted in decreased de novo lipogenesis and lipid droplet accumulation in cultured adipocytes. 6 To further understand the role of MBOA-1/ACAT in lipid metabolism, we investigated the effect of pharmacological inhibition of MBOA-1/ACAT on fat accumulation and fastinginduced fat mobilization in C. elegans using Avasimibe (Ava), an ACAT inhibitor developed for the treatment of cardiovascular diseases. 29 First, we examined the effect Ava on fat accumulation in high-fat C. elegans constructed by glucose administration.…”

“…in decreased de novo lipogenesis in cultured adipocytes, thereby reducing lipid droplet formation. 6 However, the physiological consequence of ACAT blockage to systemic lipid metabolism is unknown.…”

HMGR overexpression and interference affect the expression of steroidogenic genes and cholesterol content in bovine intramuscular adipocytes

“…Adipose tissue is the major depot for energy and cholesterol storage, with most of the intracellular cholesterol distributed in the form of lipid droplets 13,14 . Cholesterol homeostasis may have a role in the regulation of adipocyte size and function 15,16 .…”