Regulation of Hepatic Glucose and Lipid Metabolism by the Acetyl‐CoA Hydrolase Acyl‐CoA Thioesterase 12 (Acot12)
Authors: Acuna‐Aravena Mariana , Cohen David E. 
Published: June 2021

Acetyl‐CoA is a key determinant of gluconeogenesis and lipid biosynthesis in the liver, and the sources of acetyl‐CoA within hepatocytes are well defined. Acot12 is a cytosolic enzyme that catalyzes the hydrolysis of acetyl‐CoA into acetate plus CoASH. In addition to its enzymatic domains, Acot12 also contains a steroidogenic acute regulatory protein‐related lipid transfer (START) domain, which functions as lipid sensor. Although enriched in the liver, the biological functions of Acot12 remain unknown. We hypothesized that Acot12 activity may suppress hepatic glucose production and lipogenesis.

Methods

To overexpress Acot12 in C57BL/6J mice and in primary cultured mouse hepatocytes, we generated Acot12.Ad adenovirus and used null.Ad adenovirus as the control. Expression levels of Acot12 were assessed by real‐time PCR, immunoblot analysis and immunofluorescence. Tolerance tests to glucose (GTTs), pyruvate (PTTs) and insulin (ITTs) were performed after 6, 16 and 4 h fasting periods, respectively. Plasma and hepatic lipid concentrations were measured using enzymatic assays. Rates of basal and cAMP‐stimulated rates of gluconeogenesis from pyruvate plus lactate, as well as de novo lipogenesis from acetate were determined in cultured hepatocytes. Fatty acid oxidation rates in liver tissue and primary hepatocytes were quantified from to the conversion of 14C‐palmitate into 14C‐acid soluble metabolites and 14C‐CO2.

Results

Acot12.Ad increased Acot12 mRNA and elevated protein levels by 10‐fold in mouse livers. Acot12 overexpression improved glucose tolerance, as evidence by decreased values of area‐under‐the curve (AUC) during the course of the GTTs. Decreased AUC values were also observed during PTTs, which reflect rates of gluconeogenesis. No differences were observed for ITTs, which largely reflect peripheral insulin responsiveness. Acot12 overexpression reduced hepatic phospholipids and plasma cholesterol concentrations. In primary hepatocytes, overexpression of Acot12 reduced basal and cAMP‐stimulated rates of glucose production, as well as rates of de novo lipogenesis. In addition, Acot12 overexpression increased fatty acid oxidation rates in both liver tissue and primary hepatocytes. This correlated with higher mRNA expression levels of the plasma membrane fatty acid transporter CD36 and of mitochondrial CPT1a, which promotes fatty acid uptake for oxidation.

Conclusions

Taken together, our findings reveal that Acot12 activity in the liver suppresses both glucose production and lipogenesis. Increased rates of hepatocellular fatty acid uptake and oxidation presumably reflect compensatory mechanisms directed towards the repletion of TCA cycle intermediates that support glucose and lipid biosynthesis. We speculate that Acot12 regulates hepatic nutrient metabolism by controlling cytosolic acetyl‐CoA concentrations within the liver.

Support or Funding Information

This work was supported by NIH grants DK048873, DK056626 and DK103046, as well as the American Liver Foundation.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.