ANGPTL8 in metabolic homeostasis: more friend than foe?

Guo, Chen; Wang, Chenxi; Deng, Xia; He, Jiekun; Yang, Licong; Yuan, Guoyue

doi:10.1098/rsob.210106

Cited by 20 publications

(21 citation statements)

References 119 publications

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“…ANGPTL8 general knockout suppresses plasma triglyceride concentrations and adiposity in mice and rats ( 31 ). Plasma ANGPTL8 concentrations are associated with obesity ( 32 ), type 2 diabetes ( 33 ), and nonalcoholic fatty liver ( 34 ). We analyzed the transcriptome data ( 21 ) of subcutaneous adipose tissue of obese patients and found that the expression of ANGPTL8 was significantly higher than the expression of ANGPTL8 of the control (healthy group), and consistent results were obtained in the liver of a high-fat diet (HFD)-induced mouse obesity model.…”

Section: Discussionmentioning

confidence: 99%

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Tang

Gao

et al. 2022

Front. Endocrinol.

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BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

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Section: Discussionmentioning

confidence: 99%

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Tang

Gao

et al. 2022

Front. Endocrinol.

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“…ANGPTL8 is an hepatokine regulated by nutritional status that plays an important role in lipid metabolism [ 21 ]. In the fed state, hepatic expression of ANGPTL8 is increased and ANGPTL8 forms hetero-complexes with ANGPTL3 in the liver and with ANGPTL4 in the adipose tissue to inhibit LPL, an enzyme that hydrolyzes TG from chylomicrons and VLDL into FFA [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, ANGPTL8 interacts with ANGPTL3 or ANGPTL4 to inhibit LPL activity [ 10 , 13 ] and several ANGPTL8 gene variants have been linked to lipid alterations [ 14 , 15 , 16 ]. Interestingly, serum ANGPTL8 concentrations are decreased in several metabolic conditions, such as obesity, T2D or dyslipidemia [ 17 , 18 , 19 ] and increase after bariatric surgery [ 20 ], although contradictory results have been published [ 21 ]. By contrast, increased circulating and hepatic expression of ANGPTL8 levels are positively associated with different stages of NAFLD [ 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Role of ANGPTL8 in NAFLD Improvement after Bariatric Surgery in Experimental and Human Obesity

Perdomo

Gómez-Ambrosi

Becerril

et al. 2021

IJMS

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Angiopoietin-like protein 8 (ANGPTL8) is an hepatokine altered in several metabolic conditions, such as obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). We sought to explore whether ANGPTL8 is involved in NAFLD amelioration after bariatric surgery in experimental models and patients with severe obesity. Plasma ANGPTL8 was measured in 170 individuals before and 6 months after bariatric surgery. Hepatic ANGPTL8 expression was evaluated in liver biopsies of patients with severe obesity undergoing bariatric surgery with available liver pathology analysis (n = 75), as well as in male Wistar rats with diet-induced obesity subjected to sham operation, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) (n = 65). The effect of ANGPTL8 on lipogenesis was assessed in human HepG2 hepatocytes under palmitate-induced lipotoxic conditions. Plasma concentrations and hepatic expression of ANGPTL8 were increased in patients with obesity-associated NAFLD in relation to the degree of hepatic steatosis. Sleeve gastrectomy and RYGB improved hepatosteatosis and reduced the hepatic ANGPTL8 expression in the preclinical model of NAFLD. Interestingly, ANGPTL8 inhibited steatosis and expression of lipogenic factors (PPARG2, SREBF1, MOGAT2 and DGAT1) in palmitate-treated human hepatocytes. Together, ANGPTL8 is involved in the resolution of NAFLD after bariatric surgery partially by the inhibition of lipogenesis in steatotic hepatocytes.

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“…VLDL levels increase due to reduced clearance and metabolic conversion under conditions of sepsis, and it is recognized that reduced lipoprotein lipase activity is a major contributor to this condition [ 7 ]. Remarkably, recent reports suggest betatrophin/ANGPTL8 as an important player regarding lipoprotein lipase inhibition and thereby the reduction of TAG clearance [ 14 , 29 ]. Under septic conditions, the latter adaptation could hypothetically augment the neutralization of inflammation-enhancing pathogen-related lipids.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, from the perspective of cardiovascular disease prevention, it had recently been discussed to be puzzling that betatrophin/ANGPTL8 has an additional function regarding the uptake of TAG in peripheral tissues, finally promoting lipid storage in AT [ 29 ]. Various previous studies including our own have reported associations of circulating betatrophin/ANGPTL8 with plasma lipids and specifically with circulating triglycerides in collectives suffering from T2D and liver steatosis (i.e., [ 13 , 30 , 31 ]).…”

Section: Discussionmentioning

confidence: 99%

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis

et al. 2022

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Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p < 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p < 0.05).

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ANGPTL8 in metabolic homeostasis: more friend than foe?

Cited by 20 publications

References 119 publications

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Role of ANGPTL8 in NAFLD Improvement after Bariatric Surgery in Experimental and Human Obesity

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis

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