Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

Abstract

In nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate within the liver because the rates of fatty acid accrual by uptake from plasma and de novo synthesis exceed elimination by mitochondrial oxidation and secretion as very low‐density lipoprotein (VLDL) triglycerides. Thioesterase superfamily member 2 (Them2) is an acyl‐coenzyme A (CoA) thioesterase that catalyzes the hydrolysis of fatty acyl‐CoAs into free fatty acids plus CoASH. Them2 is highly expressed in the liver, as well as other oxidative tissues. Mice globally lacking Them2 are resistant to diet‐induced obesity and hepatic steatosis, and exhibit improved glucose homeostasis. These phenotypes are attributable, at least in part, to roles of Them2 in the suppression of thermogenesis in brown adipose tissue and insulin signaling in skeletal muscle. To elucidate the hepatic function of Them2, we created mice with liver‐specific deletion of Them2 (L‐Them2‐/‐). Although L‐Them2‐/‐ mice were not protected against excess weight gain, hepatic steatosis or glucose intolerance, they exhibited marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These were attributable to reduced rates of VLDL secretion owing to decreased incorporation of plasma‐derived fatty acids into triglycerides. The absence of hepatic steatosis in L‐Them2‐/‐ mice fed chow was explained by compensatory increases in rates of fatty acid oxidation and by decreased de novo lipogenesis in high fat–fed mice. Consistent with a role for Them2 in hepatic VLDL secretion, THEM2 levels were increased in livers of obese patients with NAFLD characterized by simple steatosis. Conclusion: Them2 functions in the liver to direct fatty acids toward triglyceride synthesis for incorporation into VLDL particles. When taken together with its functions in brown adipose and muscle, these findings suggest that Them2 is a target for the management of NAFLD and dyslipidemia.

Acyl‐Coenzyme A Thioesterase 9 Traffics Mitochondrial Short‐Chain Fatty Acids Toward De Novo Lipogenesis and Glucose Production in the Liver

“…(5)(6)(7)(8)(9) Whereas the perpetual actions of 26 Acs and 15 Acot family members maintain lipid homeostasis in health, we have shown that obesity-induced activation of Acots, in response to excess fatty acids, can instead traffic excess acyl-CoA toward lipotoxic pathways, such as increased accumulation of saturated phospholipids and VLDL secretion. (8,9) In the current study, we demonstrate that hepatic Acot9 (synonym: mt-Act48, mitochondrial Acot of 48 kDa) expression increases in the setting of NAFLD in mice and patients with obesity. Despite exhibiting broad substrate specificity in vitro, Acot9 is a mitochondrial protein that is enriched in many oxidative tissues and represents the main short-chain Acot within the mitochondria.…”

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

“…Equal volumes of plasma were pooled from three mice and lipoproteins were fractionated by fast protein liquid chromatography (ÄKTA pure FPLC system, GE Healthcare, Pittsburgh, PA, USA) and triglyceride and cholesterol in fractions quantified with reagent kits (Wako Diagnostics, Mountain View, CA). 68,69 Liver histology and quantification (CF and MP), using the NAS system from NASH-CRN. 39 Steatosis grade (0 :< 5%, 1: 5-33%, 2:…”

The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

“…Moreover, PCTP, upon complexing with PC, binds and enhances the enzymatic activity of the thioesterase superfamily member 2 (Them2), a mitochondria-associated long-chain acyl-CoA thioesterase. Them2 is also highly expressed in the liver and plays a key role in the rerouting of fatty acids from β-oxidation to glycerolipid biosynthesis [32]. Therefore, induction of PCTP by VDR could favor Them2 activity and hence the redirection of fatty acids toward TG synthesis.…”