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

Ersoy, Baran A.; Maner-Smith, Kristal; Li, Yingxia; Alpertunga, Ipek; Cohen, David E.

doi:10.1172/jci93123

Cited by 33 publications

(48 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By these mechanisms, Them2 functions within BAT to limit adaptive thermogenesis . In addition, studies in vitro have demonstrated that Them2 expression in hepatocytes suppresses insulin signaling, while promoting FA oxidation and gluconeogenesis . Based on these observations, we ascribed the enhanced insulin sensitivity and improved glucose homeostasis observed in Them2 ‐/‐ mice primarily to functions of Them2 within the liver .…”

Section: Discussionmentioning

confidence: 85%

“…In this connection, in cultured mouse hepatocytes under nutrient restriction, changes in PC composition of cellular membranes lead to the formation of Them2/PC‐TP complex, which directly suppresses mTORC1 signaling by interacting with tuberous sclerosis complex 2 (TSC2) to stabilize the TSC1‐TSC2 complex . However, when FAs are abundant, the Them2/PC‐TP complex functions to promote the synthesis of PC for ER membranes . Taken together, these findings provide a plausible mechanism by which Them2/PC‐TP interactions are modulated in response to nutritional status and may function to (1) sustain PC synthesis and facilitate the lipidation of nascent VLDL particles within the ER when lipid substrates are available, and (2) suppress mTORC1 signaling, leading to reduced CCTα activity and decreased VLDL secretion following more severe nutrient deprivation, potentially contributing to the hepatic steatosis associated with prolonged fasting …”

Section: Discussionmentioning

confidence: 89%

“…Them2 was identified as an interacting partner for phosphatidylcholine transfer protein (PC‐TP) in the liver . Mechanistic studies in cultured mouse hepatocytes revealed both PC‐TP‐dependent and PC‐TP‐independent functions for Them2 . Under conditions simulating fasting, Them2/PC‐TP complex promotes FA oxidation in vitro .…”

mentioning

confidence: 99%

“…Them2 ‐/‐ mice are protected against diet‐induced obesity and exhibit decreased adiposity, reduced hepatic glucose production, enhanced hepatic insulin sensitivity, and resistance to high‐fat diet–induced hepatic steatosis . In the setting of overnutrition, hepatic Them2 promotes the channeling of saturated FA into endoplasmic reticulum (ER) membrane phospholipids, which reduce membrane fluidity and promote calcium efflux into the cytosol . This activates the unfolded protein response, leading to increases in hepatic insulin resistance and glucose production .…”

mentioning

confidence: 99%

“…(5) Mechanistic studies in cultured mouse hepatocytes revealed both PC-TP-dependent and PC-TP-independent functions for Them2. (6)(7)(8) Under conditions simulating fasting, Them2/PC-TP complex promotes FA oxidation in vitro. However, when cells are cultured under high glucose concentrations, Them2 in the absence of PC-TP expression is sufficient to induce glucose oxidation and lipogenesis.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

show abstract

Emerging Targets in Type 2 Diabetes and Diabetic Complications

et al. 2021

View full text Add to dashboard Cite

Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment-or even the prevention-of type 2 diabetes along with its complications.

show abstract

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background and Aims Obesity‐induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) that is due to excess fatty acids. Acyl‐coenzyme A (CoA) thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl‐CoA into nonesterified fatty acids and CoASH. Approach and Results Using Caenorhabditis elegans, we identified Acot9 as the strongest regulator of lipid accumulation within the Acot family. Indicative of a maladaptive function, hepatic Acot9 expression was higher in patients with obesity who had NAFLD and NASH compared with healthy controls with obesity. In the setting of excessive nutrition, global ablation of Acot9 protected mice against increases in weight gain, HGP, steatosis, and steatohepatitis. Supportive of a hepatic function, the liver‐specific deletion of Acot9 inhibited HGP and steatosis in mice without affecting diet‐induced weight gain. By contrast, the rescue of Acot9 expression only in the livers of Acot9 knockout mice was sufficient to promote HGP and steatosis. Mechanistically, hepatic Acot9 localized to the inner mitochondrial membrane, where it deactivated short‐chain but not long‐chain fatty acyl‐CoA. This unique localization and activity of Acot9 directed acetyl‐CoA away from protein lysine acetylation and toward the citric acid (TCA) cycle. Acot9‐mediated exacerbation of triglyceride and glucose biosynthesis was attributable at least in part to increased TCA cycle activity, which provided substrates for HGP and DNL. β‐oxidation and ketone body production, which depend on long‐chain fatty acyl‐CoA, were not regulated by Acot9. Conclusions Taken together, our findings indicate that Acot9 channels hepatic acyl‐CoAs toward increased HGP and DNL under the pathophysiology of obesity. Therefore, Acot9 represents a target for the management of NAFLD.

show abstract

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

Cited by 33 publications

References 63 publications

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

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

Emerging Targets in Type 2 Diabetes and Diabetic Complications

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

Contact Info

Product

Resources

About