Abstract
Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure. Lower Them1 expression levels in the liver are upregulated in response to high-fat feeding. Them1-/- mice are resistant to diet-induced obesity, hepatic steatosis, and glucose intolerance, but the contribution of Them1 in liver is unclear. To examine its liver-specific functions, we created conditional transgenic mice, which, when bred to Them1-/- mice and activated, expressed Them1 exclusively in the liver. Mice with liver-specific Them1 expression exhibited no changes in energy expenditure. Rates of fatty acid oxidation were increased, whereas hepatic VLDL triglyceride secretion rates were decreased by hepatic Them1 expression. When fed a high-fat diet, Them1 expression in liver promoted excess steatosis in the setting of reduced rates of fatty acid oxidation and preserved glycerolipid synthesis. Liver-specific Them1 expression did not influence glucose tolerance or insulin sensitivity, but did promote hepatic gluconeogenesis in high-fat-fed animals. This was attributable to the generation of excess fatty acids, which activated PPARα and promoted expression of gluconeogenic genes. These findings reveal a regulatory role for Them1 in hepatocellular fatty acid trafficking.
Highlights
Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure
Measurement of acyl-CoA thioesterase (ACOT) activity provided evidence for the overexpression of active enzyme: no differences in Km were detected among genotypes, there was a 25% increase in Vmax values of liver homogenates from KO + LTg mice compared with the WT controls
This study was designed to understand the specific functions of Them1 in liver and the extent to which these contribute to the phenotypes observed in Them1 / mice [4, 5], especially the improved metabolic profiles exhibited in high-fat-fed animals [4]
Summary
Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure. When fed a high-fat diet, Them expression in liver promoted excess steatosis in the setting of reduced rates of fatty acid oxidation and preserved glycerolipid synthesis. Liver-specific Them expression did not influence glucose tolerance or insulin sensitivity, but did promote hepatic gluconeogenesis in high-fat-fed animals. This was attributable to the generation of excess fatty acids, which activated PPAR and promoted expression of gluconeogenic genes. Thioesterase superfamily member 1 (Them1) [synonyms: brown fat inducible thioesterase (BFIT), steroidogenic acute regulatory protein-related lipid transfer (START) domain 14 (StarD14)/Acot11] is enriched in mouse brown adipose tissue (BAT), and its expression is markedly upregulated by cold ambient temperatures [3, 4]. Upon uptake or synthesis within hepatocytes, long-chain FFAs are activated by long-chain acyl-CoA synthetases (ACSLs) to form fatty acyl-CoA molecules, which may
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