Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

Tillander, Veronika; Alexson, Stefan E.H.; Cohen, David E.

doi:10.1016/j.tem.2017.03.001

Cited by 121 publications

(147 citation statements)

References 79 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…In addition, the suppression of ER stress in the absence of Them2 or PC-TP expression prevented the downstream activation of CHOP, and this presumably contributed to improved hepatic insulin sensitivity observed in high-fatfed Them2 -/-and Pctp -/-mice (15,17). We have proposed that the Them2/PC-TP complex plays an important role in the selection and trafficking of fatty acids into oxidative or glycerolipid biosynthetic pathways (20). Our current findings provide a plausible mechanism for our previous observations in cultured hepatocytes that, under physiological conditions, PC-TP and Them2 interactions increase in response to fasting and function to promote hepatic glucose production (19).…”

Section: Animals and Experimental Induction Of Er Stress Male Pctp +mentioning

confidence: 96%

“…We have postulated that this complex channels fatty acids to glycerol-phosphate acyl transferase 1 (GPAT1), a mitochondria-associated enzyme that represents the rate-controlling step in glycerolipid synthesis, including ER membrane phospholipids (20). Our current findings demonstrate that, by promoting the incorporation of SFAs into ER membrane phospholipids, the Them2/PC-TP complex reduces membrane fluidity, increases calcium efflux through translocons within the ER membrane, and activates ER stress pathways that promote insulin resistance and excess hepatic glucose production.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

Ersoy¹,

Maner-Smith²,

Li³

et al. 2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Section: Animals and Experimental Induction Of Er Stress Male Pctp +mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

Ersoy¹,

Maner-Smith²,

Li³

et al. 2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…These enzymes catalyze the hydrolysis of acyl-CoA molecules into FA and CoA. Despite their relatively well-investigated enzymatic activities, the biological functions of the fifteen ACOT family members remain less well understood (53, 142, 256). Acots 1–6 , which constitute the type I enzymes, are upregulated in the livers of fasted and high fat-fed mice under the transcriptional control of PPARα (79).…”

Section: Introductionmentioning

confidence: 99%

Triglyceride Metabolism in the Liver

Auger

Cohen

2017

Comprehensive Physiology

Self Cite

522

551

View full text Add to dashboard Cite

Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.

show abstract

“…Although the mechanisms that control the dispositions of long‐chain FAs are incompletely understood, their entry into nearly all metabolic pathways requires activation to fatty acyl‐coenzyme A (CoA). This reaction is catalyzed by long‐chain acyl‐CoA synthetases (ACSLs) and is reversed by acyl‐CoA thioesterases (ACOTs) . Multiple ACSL and ACOT isoforms are expressed in cells, and emerging evidence suggests key roles for these enzymes in the regulation of intracellular FA channeling …”

mentioning

confidence: 99%

“…This reaction is catalyzed by long-chain acyl-CoA synthetases (ACSLs) and is reversed by acyl-CoA thioesterases (ACOTs). (2,3) Multiple ACSL and ACOT isoforms are expressed in cells, and emerging evidence suggests key roles for these enzymes in the regulation of intracellular FA channeling. (2) Thioesterase superfamily member 2 (Them2, synonymous with ACOT13) is a mitochondria-associated ACOT with substrate specificity for medium-and long-chain acyl-CoAs.…”

mentioning

confidence: 99%

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

Auger

Acuña

et al. 2019

Hepatology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

Cited by 121 publications

References 79 publications

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

Triglyceride Metabolism in the Liver

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

Contact Info

Product

Resources

About