Adipose Triglyceride Lipase Research Articles

Role of diacylglycerol O-acyltransferase 1 (DGAT1) in lipolysis and autophagy of adipose tissue from ketotic dairy cows

High-yielding dairy cows in early lactation often encounter difficulties in meeting the energy requirements essential for maintaining milk production. This is primarily attributed to insufficient dry matter intake, which consequently leads to sustained lipolysis of adipose tissue. Fatty acids released by lipolysis can disrupt metabolic homeostasis. Autophagy, an adaptive response to intracellular environmental changes, is considered a crucial mechanism for regulating lipid metabolism and maintaining a proper cellular energy status. Despite its close relationship with aberrant lipid metabolism and cytolipotoxicity in animal models of metabolic disorders, the precise function of diacylglycerol o-acyltransferase 1 (DGAT1) in bovine adipose tissue during periods of negative energy balance is not fully understood, particularly regarding its involvement in lipolysis and autophagy. The objective of the present study was to assess the effect of DGAT1 on both lipolysis and autophagy in bovine adipose tissue and isolated adipocytes. Adipose tissue and blood samples were collected from cows diagnosed as clinically ketotic (n = 15) or healthy (n = 15) following a veterinary evaluation based on clinical symptoms and serum concentrations of BHB, which were 3.19 mM (interquartile range = 0.20) and 0.50 mM (interquartile range = 0.06), respectively. Protein abundance of DGAT1 and phosphorylation levels of unc-51-like kinase 1 (ULK1), were greater in adipose tissue from cows with ketosis, whereas phosphorylation levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were lower. Furthermore, when adipocytes isolated from the harvested adipose tissue of 15 healthy cows were transfected with DGAT1 overexpression adenovirus or DGAT1 small interfering RNA followed by exposure to epinephrine (EPI), it led to greater ratios and protein abundance of phosphorylated hormone-sensitive triglyceride lipase (LIPE) to total LIPE and adipose triglyceride lipase (ATGL), while inhibiting the protein phosphorylation levels of ULK1, PI3K, AKT, and mTOR. Overexpression of DGAT1 in EPI-treated adipocytes reduced lipolysis and autophagy, whereas silencing DGAT1 further exacerbated EPI-induced lipolysis and autophagy. Taken together, these findings indicate that upregulation of DGAT1 may function as an adaptive response to suppress adipocytes lipolysis, highlighting the significance of maintaining metabolic homeostasis in dairy cows during periods of negative energy balance.

The loss of antioxidant activities impairs intestinal epithelium homeostasis by altering lipid metabolism

Reactive oxygens species (ROS) are common byproducts of metabolic reactions and could be at the origin of many diseases of the elderly. Here we investigated the role of ROS in the renewal of the intestinal epithelium in mice lacking catalase (CAT) and/or nicotinamide nucleotide transhydrogenase (NNT) activities. Cat−/− mice have delayed intestinal epithelium renewal and were prone to develop necrotizing enterocolitis upon starvation. Interestingly, crypts lacking CAT showed fewer intestinal stem cells (ISC) and lower stem cell activity than wild-type. In contrast, crypts lacking NNT showed a similar number of ISCs as wild-type but increased stem cell activity, which was also impaired by the loss of CAT. No alteration in the number of Paneth cells (PCs) was observed in crypts of either Cat−/− or Nnt−/− mice, but they showed an evident decline in the amount of lysozyme. Cat deficiency caused fat accumulation in crypts, and a fall in the remarkable high amount of adipose triglyceride lipase (ATGL) in PCs. Notably, the low levels of ATGL in the intestine of Cat −/− mice increased after a treatment with the antioxidant N-acetyl-L-cysteine. Supporting a role of ATGL in the regulation of ISC activity, its inhibition halt intestinal organoid development. These data suggest that the reduction in the renewal capacity of intestine originates from fatty acid metabolic alterations caused by peroxisomal ROS.

Phillyrin: an adipose triglyceride lipase inhibitor supported by molecular docking, dynamics simulation, and pharmacological validation.

Adipose triglyceride lipase (ATGL), a key enzyme responsible for lipolysis, catalyzes the first step of lipolysis and converts triglycerides to diacylglycerols and free fatty acids (FFA). Our previous work suggested that phillyrin treatment improves insulin resistance in HFD-fed mice, which was associated with ATGL inhibition. In this study, using docking simulation, we explored the binding pose of phillyrin and atglistatin (a mouse ATGL inhibitor) to ATGL in mouse. From the docking results, the interactions with Ser47 and Asp166 were speculated to have caused phillyrin to inhibit ATGL in mice. Further, molecular dynamics simulation of 100 ns and MM-GBSA were conducted for the protein-ligand complex, which indicated that the system was stable and that phillyrin displayed a better affinity to ATGL than did atglistatin throughout the simulation period. Moreover, the results of pharmacological validation were consistent with those of the in silico simulations. In summary, our study illustrates the potential of molecular docking to accurately predict the binding protein produced by AlphaFold and suggests that phillyrin is a potential small molecule that targets and inhibits ATGL enzymatic activity. The ATGL-predicted protein structure, verified by PROCHECK, was determined using AlphaFold. Molecular docking, molecular dynamics simulation, and prime molecular mechanic-generalized born surface area were performed using LigPrep, Desmond, and prime MM-GBSA modules of Schrödinger software release 2021-2, respectively. For pharmacological validation, immunoblotting was performed to assess ATGL protein expression. The fluorescence intensity and glycerol concentration were quantified to evaluate the efficiency of phillyrin in inhibiting ATGL.

Microbe-derived Antioxidants Enhance Lipid Synthesis by Regulating the Hepatic AMPKα–SREBP1c Pathway in Weanling Piglets

BackgroundWeaning usually causes low feed intake and weight loss in piglets, which mobilizes lipid to energize. The microbe-derived antioxidants (MAs) exhibit great potential in antioxidation, anti-inflammation, and metabolic regulation. ObjectivesWe aimed to investigate the changes of lipid metabolism postweaning and effects of MA on growth performance and hepatic lipid metabolism in weanling piglets. MethodsIn the first experiment, piglets weaned at 21 d of age were slaughtered on weaning day (d0), 4 (d4), and 14 (d14) postweaning (6 piglets per day). In the second experiment, piglets were divided into 2 groups, receiving MA (MA) and saline gavage (CON), respectively. All piglets were weaned at 21 d of age and 6 piglets from each group were slaughtered at 25 d of age. ResultsIn experiment 1, the serum triglyceride, total cholesterol (TC), and LDL cholesterol on d4 and d14 declined significantly compared with d0 (P < 0.05). The serum leptin on d0 was higher than that on d4 and d14 (P < 0.05). The serum ghrelin kept increasing from d0 to d14 (P < 0.05). The hepatic hormone-sensitive lipase and adipose triglyceride lipase first increased from d0 to d4 and then decreased from d4 to d14 (P < 0.05). In experiment 2, the average daily gain and average daily feed intake from 21 to 25 d of age increased in the MA group compared with the CON group (P < 0.05). The serum TC, hepatic TC, and glucose of MA group showed a significant increase than that of the CON group (P < 0.05). The expression of SCD1, ACAT2, and PPARγ were upregulated in the MA group (P < 0.05). Contrary to the decreased expression of phosphorylation of adenosine 5′-monophosphate-activated protein kinase alfa subunit (Thr172), the nuclear sterol regulatory element–binding protein 1c, fatty acid synthase, and peroxisome proliferator-activated receptor gamma of MA group increased than that of CON group (P < 0.05). ConclusionsWeaning promoted hepatic lipolysis and MA could enhance lipid synthesis by regulating adenosine 5′-monophosphate-activated protein kinase alfa subunit–sterol regulatory element–binding protein 1c pathway, thus improving growth performance of weanling piglets.

Effects of Clostridium tyrobutyricum on Lipid Metabolism, Intestinal Barrier Function, and Gut Microbiota in Obese Mice Induced by High-Fat Diet.

Obesity and its complications constitute a main threat to global human health. The purpose of this investigation was to explore the influences of Clostridium tyrobutyricum (Ct) on lipid metabolism, intestinal barrier function, and intestinal microbiome in obese mice induced by a high-fat diet (HFD). After establishing the obesity model, 107 CFU/mL and 108 CFU/mL C. tyrobutyricum were used to intervene in HFD-fed mice by gavage for six weeks, and indexes related to obesity were measured. In the liver of HFD-fed mice, the results revealed that C. tyrobutyricum reduced liver weight and the levels of triglyceride (TG), total cholesterol (TC), and nonesterified fatty acid (NEFA), along with decreasing red lipid droplets and fat vacuoles. After C. tyrobutyricum intervention, the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) was downregulated, and AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPARα), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) were upregulated in the liver. Additionally, C. tyrobutyricum alleviated intestinal morphology injury caused by HFD, decreased the expression of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-1β in the colon, and upregulated tight junction protein expression. In addition, 16S rRNA sequencing revealed that C. tyrobutyricum increases the diversity of intestinal microbiota. Overall, C. tyrobutyricum improved HFD-induced lipid metabolism disorders, preserved the intestinal barrier's integrity, and modulated the structure of the intestinal microbiome. These findings provide a novel insight into the role of C. tyrobutyricum as a probiotic in regulating lipid metabolism.

Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice.

Gypenoside XIII is isolated from Gynostemma pentaphyllum (Thunb.) Makino. In mice, G. pentaphyllum extract and gypenoside LXXV have been shown to improve non-alcoholic steatohepatitis (NASH). This study investigated whether gypenoside XIII can regulate lipid accumulation in fatty liver cells or attenuate NASH in mice. We used HepG2 hepatocytes to establish a fatty liver cell model using 0.5 mM oleic acid. Fatty liver cells were treated with different concentrations of gypenoside XIII to evaluate the molecular mechanisms of lipid metabolism. In addition, a methionine/choline-deficient diet induced NASH in C57BL/6 mice, which were given 10 mg/kg gypenoside XIII by intraperitoneal injection. In fatty liver cells, gypenoside XIII effectively suppressed lipid accumulation and lipid peroxidation. Furthermore, gypenoside XIII significantly increased SIRT1 and AMPK phosphorylation to decrease acetyl-CoA carboxylase phosphorylation, reducing fatty acid synthesis activity. Gypenoside XIII also decreased lipogenesis by suppressing sterol regulatory element-binding protein 1c and fatty acid synthase production. Gypenoside XIII also increased lipolysis and fatty acid β-oxidation by promoting adipose triglyceride lipase and carnitine palmitoyltransferase 1, respectively. In an animal model of NASH, gypenoside XIII effectively decreased the lipid vacuole size and number and reduced liver fibrosis and inflammation. These findings suggest that gypenoside XIII can regulate lipid metabolism in fatty liver cells and improve liver fibrosis in NASH mice. Therefore, gypenoside XIII has potential as a novel agent for the treatment of NASH.

Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity

ObjectiveLipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. MethodsMale and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. ResultsAll groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. ConclusionsTAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.

PGC-1α activation boosts exercise-dependent cellular response in the skeletal muscle

The role of Peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) in fat metabolism is not well known. In this study, we compared the mechanisms of muscle-specific PGC-1α overexpression and exercise-related adaptation-dependent fat metabolism. PGC-1α trained (PGC-1α Ex) and wild-trained (wt-ex) mice were trained for 10 weeks, five times a week at 30 min per day with 60 percent of their maximal running capacity. The PGC-1α overexpressed animals exhibited higher levels of Fibronectin type III domain-containing protein 5 (FNDC5), 5' adenosine monophosphate-activated protein kinase alpha (AMPK-α), the mammalian target of rapamycin (mTOR), Sirtuin 1 (SIRT1), Lon protease homolog 1 (LONP1), citrate synthase (CS), succinate dehydrogenase complex flavoprotein subunit A (SDHA), Mitofusin-1 (Mfn1), endothelial nitric oxide synthase (eNOS), Hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), G protein-coupled receptor 41 (GPR41), and Phosphatidylcholine Cytidylyltransferase 2 (PCYT2), and lower levels of Sirtuin 3 (SIRT3) compared to wild-type animals. Exercise training increased the protein content levels of SIRT1, HSL, and ATGL in both the wt-ex and PGC-1α trained groups. PGC-1α has a complex role in cellular signaling, including the upregulation of lipid metabolism-associated proteins. Our data reveals that although exercise training mimics the effects of PGC-1α overexpression, it incorporates some PGC-1α-independent adaptive mechanisms in fat uptake and cell signaling.

Metabolic remodeling of visceral and subcutaneous white adipose tissue during reacclimation of rats after cold.

Deciphering lipid metabolism in white adipose tissue (WAT) depots during weight gain is important to understand the heterogeneity of WAT and its roles in obesity. Here, we examined the expression of key enzymes of lipid metabolism and changes in the morphology of representative visceral (epididymal) and subcutaneous (inguinal) WAT (eWAT and iWAT, respectively)-in adult male rats acclimated to cold (4 ± 1°C) for 45 days and reacclimated to room temperature (RT, 22 ± 1°C) for 1, 3, 7, 12, 21, or 45 days. The relative mass of both depots decreased to a similar extent after cold acclimation. However, fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), and medium-chain acyl-CoA dehydrogenase (ACADM) protein level increased only in eWAT, whereas adipose triglyceride lipase (ATGL) expression increased only in iWAT. During reacclimation, the relative mass of eWAT reached control values on day 12 and that of iWAT on day 45 of reacclimation. The faster recovery of eWAT mass is associated with higher expression of FAS, acetyl-CoA carboxylase (ACC), G6PDH, and ACADM during reacclimation and a delayed increase in ATGL. The absence of an increase in proliferating cell nuclear antigen suggests that the observed depot-specific mass increase is predominantly due to metabolic adjustments. In summary, this study shows a differential rate of visceral and subcutaneous adipose tissue weight regain during post-cold reacclimation of rats at RT. Faster recovery of the visceral WAT as compared to subcutaneous WAT during reacclimation at RT could be attributed to observed differences in the expression patterns of lipid metabolic enzymes.

Nutritional and physiological responses of female and male largemouth bass (Micropterus salmoides) to different dietary starch levels

In this study, we adopted a 2 × 2 factorial design incorporating different dietary starch levels and sexes to assess the impact of dietary starch on the growth performance, feeding response, and glucolipid metabolism of female and male largemouth bass. Two isonitrogenous (49.6%) and isolipidic (10.4%) diets were formulated with 10% starch (low-starch level) and 20% starch (high-starch level). The results indicated that male largemouth bass exhibited superior growth performance compared to females regardless of the dietary starch levels. Furthermore, males demonstrated enhanced feed utilization of the high-starch diet compared to females. Males also exhibited significantly lower mRNA expressions of feeding inhibition molecules (cholecystokinin, leptin b, leptin b receptor, or cocaine and amphetamine-regulated transcript 2) in the brain compared to females, a phenomenon unrelated to dietary starch levels. Compared to females, males fed the high-starch diet displayed elevated mRNA expression of genes associated with glycolysis (hexokinase, pyruvate kinase, and phosphofructokinase) in the liver, as well as lower expression of gluconeogenesis-related genes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), which coincided with lower hepatic glycogen in males. Furthermore, males fed with the high-starch diet exhibited higher mRNA expression of genes involved in hepatic lipid catabolism (carnitine palmitoyl transferase 1, hormone-sensitive lipase, and adipose triglyceride lipase). In contrast, males exhibited lower expression of hepatic lipid synthesis regulation (acetyl-CoA carboxylase 1, peroxisome proliferator-activated receptor γ, and fatty acid synthase) in the liver compared with females fed with the low-starch diet. Additionally, upon comparing the hepatic transcriptomes of males and females fed with the high-starch diet, the males exhibited a significant up-regulation of glucokinase2 and hexokinase, coupled with down-regulation of glucose-6-phosphatase. In summary, male largemouth bass exhibited superior growth performance at this developmental stage compared to females regardless of dietary starch levels. Males also exhibited higher feed utilization when fed the high-starch diet, which was likely due to increased activity in glycolytic processes and enhanced fatty acid decomposition compared to females.

Prevention of high-fat-diet-induced obesity in mice by soluble dietary fiber from fermented and unfermented millet bran

Obesity-related diabetes, cardiovascular disease, and hypertension pose many risks to human health. Thus, mice on a high-fat diet were gavaged with millet bran (unfermented/fermented) soluble dietary fiber (RSDF/FSDF, 500 mg·kg−1) for 10 weeks in current research, and then evaluated the various biological indicators. These findings revealed that RSDF and FSDF supplements could prevent fat synthesis by inhibiting sterol regulatory element-binding protein-1c gene expression. The RSDF supplements can also accelerate fat catabolism through enhanced the mRNA expression levels of adipose triglyceride lipase and peroxisome proliferator-activated receptor α. FSDF supplements can prevent obesity by decreasing 3-hydroxy-3-methyl-glutaryl-CoA reductase expression and increasing cholesterol 7α-hydroxylase expression. Moreover, FSDF also controls obesity development by lowering total cholesterol and low-density lipoprotein cholesterol levels in the blood, triglyceride, total cholesterol, and bile acid levels in the liver. Notably, FSDF supplements can promote Bacteroides and Prevotella propagation; excretive propionic acid binds to free fatty acid receptor 2/3 and then stimulates intestinal epithelial cells to generate glucagon-like-peptide-1 and peptide YY, which can reduce food and energy intake and ultimately prevent obesity. All evidence suggests that FSDF supplements play a crucial role in preventing obesity.

Effects of riboflavin deficiency and high dietary fat on hepatic lipid accumulation: a synergetic action in the development of non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored.MethodsIn the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique.ResultsThe results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load.ConclusionsThere is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.

Taurine supplementation decreases fat accumulation by suppressing FAS and enhancing ATGL through the ATGL pathway.

Obesity leads to severe health issues like cardiovascular disease. Natural substances with anti-obesity properties are gaining attention. This study investigates the impact of taurine on lipid levels in rats fed a high-fat diet. The SD rats were fed a high-fat diet and treated with or without taurine for 21 weeks. Taurine was added to their drinking water, and an adipose triglyceride lipase (ATGL) inhibitor was injected for one week. The study evaluated the impact of taurine supplementation on the rats' body weight, Lee index, body fat content, serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), fatty acid synthase (FAS), ATGL, and peroxisome proliferator-activated receptor α (PPARα) in the liver. Fat accumulation in the liver and aortic arch was assessed through histopathological observations. The study found that taurine reduced body weight, body fat, serum TG, TC, LDL-C levels, and lipid deposition in the liver and aortic arch while increasing serum HDL-C levels. Taurine intake also increased FAS and ATGL expression in the liver. Interestingly, the ATGL inhibitor atglistatin did not affect FAS and ATGL expression in the presence of taurine. Taurine can reduce fat deposition caused by a high-fat diet in SD rats by decreasing FAS content and increasing ATGL content. However, taurine does not fully regulate FAS and ATGL expression through the ATGL pathway.

ABHD5 as a friend or an enemy in cancer biology?

Alpha beta hydrolase domain containing 5 (ABHD5) is an essential coactivator of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in various cell types that promotes the hydrolysis of triacylglycerol (TG) into diacylglycerol (DG) and fatty acid (FA). It acts as a critical regulatory factor in cellular lipid metabolism. The reprogramming of lipid metabolism is one of the hallmarks of cancer, suggesting that altering lipid metabolism could become a new strategy for tumor treatment. Research has revealed a close association between ABHD5 and the development and progression of malignancies. This review summarizes the role of ABHD5 in various malignant tumors and explores the different signaling pathways and metabolic routes that may be involved, providing a comprehensive mechanistic understanding of ABHD5.

Neutral lipid storage disease with myopathy: clinicopathological and genetic features of nine Iranian patients

The rare disorder known as Neutral Lipid Storage Disease with Myopathy presents with a variety of clinical manifestations, including myopathy, cardiac dysfunction, and other organ complications. Early diagnosis is crucial due to the increased risk of cardiomyopathy. We describe the clinical, histopathological, muscle imaging, and genetic findings of nine neutral lipid storage myopathy patients. Proximal weakness and asymmetric involvement may suggest lipid storage myopathy. While skeletal muscle weakness was the main manifestation in our patients, one case presented only with hyperCKemia. Additionally, three patients had fertility issues, two suffered from diabetes mellitus, two had cardiomyopathy, and one had a history of hypothyroidism. Muscle histopathology revealed lipid depositions and rimmed vacuoles, prompting peripheral blood smears to detect Jordan Anomalies. All muscle biopsies and peripheral blood smear showed lipid droplets, rimmed vacuoles, and Jordan anomaly. Identifying PNPLA2 gene mutations is important for diagnosing neutral lipid storage myopathy; our cases showed some novel mutations. This study highlights the importance of early diagnosis and comprehensive evaluation in managing neutral lipid storage myopathy cases.

Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58

Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be coactivated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein coactivation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for coactivation by CGI-58. ATGL variants with amino acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 coactivation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the coactivation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for coactivation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58–mediated coactivation of ATGL.

Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells.

Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 μM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.

Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis.

E3 ubiquitin ligase, Constitutive Photomorphogenic 1 (COP1) regulates turnover of Adipose Triglyceride Lipase (ATGL), the rate-limiting lipolytic enzyme. Genetic perturbation in the COP1-ATGL axis disrupts lipid homeostasis, leading to liver steatosis. Using drug development strategies, we herein report quinazolinone and quinazolinedione based modulators for COP1-ATGL axis. Systematic SAR studies and subsequent optimization were performed by incorporating relevant functional groups at the N1, N3, C5, and C6 positions of both scaffolds. Compounds' efficacy was evaluated by multiple biological assays and ADME profiling. The lead compound 86 could increase ATGL protein expression, reduce ATGL ubiquitination and COP1 autoubiquitination, and diminish lipid accumulation in hepatocytes in the nanomolar range. Oral administration of 86 abrogated triglyceride accumulation and resolved fibrosis in preclinical Nonalcoholic Fatty Liver Disease (NAFLD) model. The study thus establishes quinazolinedione as a viable chemotype to therapeutically modulate the activity of COP1 and ATGL in relevant clinical contexts.

Effects of Light and Feeding on Expressions of Clock Genes and Metabolic Genes in the Ridgetail Shrimp, Exopalaemon carinicauda

The changes of the circadian clock genes expression, growth, and muscle composition in Exopalaemon carinicauda under different photoperiods and feeding time were investigated by real-time fluorescence quantitative PCR and muscle biochemical composition analysis, respectively. Results showed that four clock genes of Clock, Cry1, Tim, and Per2 showed significant circadian rhythms in both eyestalk and hepatopancreas. Their expression rhythms were highly correlated with the photoperiod in the eyestalk, but in the hepatopancreas, it was significantly correlated with the feeding time. Moreover, the expressions of several metabolic genes were also variable; adipose triglyceride lipase (ATGL) and amyloglucosidase (AGL) changed significantly with the shift of feeding time, whereas methionine synthase (MS) and succinate dehydrogenase (SDH) changed significantly with the photoperiod. This reflected the close relationship between the metabolic and circadian clock in E. carinicauda; Alterations in photoperiod or feeding time lead to changes in the biological clock systems, which affects the daily expression of metabolic genes at the downstream metabolic pathway and closely correlates their expression rhythms with epi-environmental factors such as feeding. It can be seen from the results that the feeding was also a significant factor that affected the crude protein and crude fat contents in muscle tissue of E. carinicauda; their highest values (18.69% ± 0.13%, 1.81% ± 0.02%) were also occurred in the treatment with feeding at 19:00. Differences in muscle composition through a similar mechanism of action, i.e., the biological clock system are affected by the feeding and then regulated changes in downstream metabolic processes. As a result, the optimized conditions for the cultivation of E. carinicauda were a short light-phase photoperiod (8L : 16D) with feeding after sunset (19:00).

Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.

ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.