Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P2 production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P2 formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.

Diacylglycerol O-acyltransferase 1 (DGAT1) is an integral membrane protein that uses acyl-coenzyme A (acyl-CoA) and diacylglycerol (DAG) to catalyze the formation of triacylglycerides (TAGs). The acyl transfer reaction occurs between the activated carboxylate group of the fatty acid and the free hydroxyl group on the glycerol backbone of DAG. However, how the two substrates enter DGAT1's catalytic reaction chamber and interact with DGAT1 remains elusive. This study aims to explore the structural basis of DGAT1's substrate recognition by investigating each substrate's pathway to the reaction chamber. Using a human DGAT1 cryo-EM structure in complex with an oleoyl-CoA substrate, we designed two different all-atom molecular dynamics (MD) simulation systems: DGAT1away (both acyl-CoA and DAG away from the reaction chamber) and DGAT1bound (acyl-CoA bound in and DAG away from the reaction chamber). Our DGAT1away simulations reveal that acyl-CoA approaches the reaction chamber via interactions with positively charged residues in transmembrane helix 7. DGAT1bound simulations show DAGs entering into the reaction chamber from the cytosol leaflet. The bound acyl-CoA's fatty acid lines up with the headgroup of DAG, which appears to be competent to TAG formation. We then converted them into TAG and coenzyme (CoA) and used adaptive biasing force (ABF) simulations to explore the egress pathways of the products. We identify their escape routes, which are aligned with their respective entry pathways. Visualization of the substrate and product pathways and their interactions with DGAT1 is expected to guide future experimental design to better understand DGAT1 structure and function.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.

Fat composition is largely responsible for the technological and rheological properties of cow milk and dairy products. Bovine milk fat is unique in terms of its fatty acid composition and positional distribution, with about 25% of its fatty acids being short- and medium-chain, which are synthesized de novo in the mammary gland and are not present in extra-mammary tissues. With the aim to identify potential genetic factors responsible for the unique composition of bovine milk fat, we extracted genes with GO annotations related to lipid metabolism and performed a gene expression mega-analysis. Overall, different lipogenic tissues (i.e., mammary, liver, and adipose) displayed discerned expression patterns. In a PCA, the liver was significantly separated from adipose and mammary tissues. In a correlation analysis with the fatty acid synthetase (FASN) gene, notable differences among the tissues were found. In the mammary gland, the majority of genes (~70%) were negatively correlated with FASN expression, whereas only 18% were negatively correlated in adipose. Only a few genes were positively correlated with FASN exclusively in the mammary gland, including AGPAT1 and AGPAT6, which also had the highest expression in the mammary gland compared with adipose. Looking at the expression levels in tissues (TPM) revealed significant differences in the expressions of genes responsible for the activation of fatty acids by ligation to CoA, according to their carbon chain length. Notably, the ACSS1 gene, which converts acetate to acetyl-CoA, had the highest expression in the mammary gland, whereas genes responsible for the activation of long-chain fatty acids had lower expressions. The findings of the present study suggest that the unique properties of dairy fat are the results of the distinct expression patterns of genes involved in de novo synthesis of fatty acids and their downstream utilization.

The lactating mammary gland strongly induces de novo lipogenesis (DNL) to support the synthesis of fatty acids, triglycerides, and cholesterol found within milk. In monogastric species, glucose is a major substrate utilized for DNL within the lactating mammary gland and must be efficiently taken up and processed to supply cytosolic acetyl-CoA for DNL. Along with the enzymes of the DNL pathway, the glycolytic enzyme, Aldolase C (Aldoc), is transcriptionally upregulated and is highly expressed during lactation in the mammary gland, suggesting a role for Aldoc in lactation. Aldoc is also a transcriptional target of the sterol regulatory element binding proteins 1 and 2 (Srebp1 and Srebp2), which transcriptionally regulate enzymes within the DNL pathway and has recently been shown to regulate plasma cholesterol and triglycerides. Here, we investigate the role of Aldoc in lactation, by utilizing a whole-body Aldoc knockout mouse. Our results demonstrate that Aldoc has a significant impact on lactation, whereby pups nursing from Aldoc-/- dams have reduced body weight. Biochemical analysis of milk identified that milk from Aldoc-/- dams have significantly higher galactose, lower lactose, and cholesterol content. Mass spectrometry analysis of milk lipids from Aldoc-/- dams revealed significantly lower quantities of medium and long chain fatty acid containing triglycerides, which has direct implications on lactation as these are the predominant triglycerides synthesized from glucose in human mammary gland. Overall, our results provide functional evidence for the contribution of Aldoc in mammary gland lactose and lipid synthesis during lactation.

In zebrafish, maternally deposited yolk is the source of nutrients for embryogenesis prior to digestive system maturation. Yolk nutrients are processed and secreted to the growing organism by an extra-embryonic tissue, the yolk syncytial layer (YSL). The export of lipids from the YSL occurs through the production of triacylglycerol-rich lipoproteins. Here we report that mutations in the triacylglycerol synthesis enzyme, diacylglycerol acyltransferase-2 (Dgat2), cause yolk sac opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. Although triacylglycerol synthesis continues, it is not properly coupled to lipoprotein production as dgat2 mutants produce fewer, smaller, ApoB-containing lipoproteins. Unlike DGAT2-null mice, which are lipopenic and die soon after birth, zebrafish dgat2 mutants are viable, fertile, and exhibit normal mass and adiposity. Residual Dgat activity cannot be explained by the activity of other known Dgat isoenzymes, as dgat1a;dgat1b;dgat2 triple mutants continue to produce YSL lipid droplets and remain viable as adults. Further, the newly identified diacylglycerol acyltransferase, Tmem68, is also not responsible for the residual triacylglycerol synthesis activity. Unlike overexpression of Dgat1a and Dgat1b, monoacylglycerol acyltransferase-3 (Mogat3b) overexpression does not rescue yolk opacity, suggesting it does not possess Dgat activity in the YSL. However, mogat3b;dgat2 double mutants exhibit increased yolk opacity and often have structural alterations of the yolk extension. Quadruple mogat3b;dgat1a;dgat1b;dgat2 mutants either have severely reduced viability and stunted growth or do not survive past 3 days post fertilization, depending on the dgat2 mutant allele present. Our study highlights the remarkable ability of vertebrates to synthesize triacylglycerol through multiple biosynthetic pathways.

The Angiopoietin-like 4 (ANGPTL4) and ETS Variant Transcription Factor 4 (ETV4) are involved in the metabolic transition and carcinogenesis in the liver. However, the role of ETV4 in the development of non-alcoholic fatty liver disease (NAFLD) is currently unknown. Our study reveals that ETV4 expression was upregulated in the diet-induced non-alcoholic fatty liver disease, and plays a critical role in the dysregulated lipid metabolism. We demonstrate a mechanism by which ANGPTL4 regulates lipid homeostasis via involving the AMPK/ETV4 axis. Transient knockdown of ETV4 abolished the ANGPTL4-induced expression of Srebp1c, Acc and Fasn. Insulin treatment potentially increased the physical association of ETV4 with SREBP1, and promotes nuclear translocation and transcriptional activity of SREBP1. In addition, we show that combined therapy with omega-3 fatty acids and diacylglycerol O-acyltransferase inhibitor 1 (DGAT1) inhibitor (A-922500) counteracted the ANGPTL4-ETV4 axis-induced lipogenesis in vitro, and in vivo in obese mice via activation of GPR120-βarrestin2-AMPK pathway. Finally, we demonstrate that targeted pharmacologic therapy using GalNac-ETV4 siRNA that specifically inhibits ETV4 gene expression in the liver protects against diet-induced NAFLD, obesity and dyslipidemia. Hence, our study reveal previously unrecognized role of ETV4 in the NAFLD, and provides rationale targeting ETV4 to treat NAFLD.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.

This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health and disease progression. Highlighting findings from both human cohorts and animal models, this review emphasizes the potential of GSLs as biomarkers and therapeutic targets. We advocate for more detailed mechanistic studies to deepen our understanding of GSL functions in cardiovascular health, which could lead to innovative strategies for diagnosis, treatment, and personalized medicine in cardiovascular care.

Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the underlying mechanisms remain to be further studied. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3' UTR of Dgat2 mRNA and intron 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3' UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.

In the small intestine, the products of digestion of dietary triacylglycerol (TAG), fatty acids (FA) and monoacylglycerol, are taken up by absorptive cells, enterocytes, for systemic energy delivery. These digestion products can also bind receptors on endocrine cells to stimulate the release of hormones capable of influencing systemic energy metabolism. The initial phase of intestinal FA absorption involves the acylation of FAs to acyl-CoA by the acyl-CoA long chain synthetase (ACSL) enzymes. ACSL5 is abundantly expressed in the small intestinal epithelium where it is the major ACSL isoform, contributing approximately 80% of total ACSL activity. In mice with whole body deficiency of ACSL5, the rate of dietary fat absorption is reduced and energy expenditure is increased. However, the mechanisms by which intestinal ACSL5 contributes to intestinal FA metabolism, enteroendocrine signaling, and regulation of energy expenditure remain undefined. Here, we test the hypothesis that intestinal ACSL5 regulates energy metabolism by influencing dietary fat absorption and enteroendocrine signaling.

To explore the role of intestinal ACSL5 in energy balance and intestinal dietary fat absorption, a novel mouse model of intestine specific ACSL5 deficiency (ACSL5IKO) was generated by breeding ACSL5 floxed (ACSL5loxP/loxP) to mice harboring the tamoxifen inducible, villin-Cre recombinase. ACSL5IKO and control, ACSL5loxP/loxP mice were fed chow (low in fat) or a 60% high fat diet (HFD), and metabolic phenotyping was performed including, body weight, body composition, insulin and glucose tolerance tests, energy expenditure, physical activity, and food intake studies. Pair-feeding studies were performed to determine the role of food intake in regulating development of obesity. Studies of dietary fat absorption, fecal lipid excretion, intestinal mucosal FA content, and circulating levels of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) in response to a TAG challenge were performed. Treatment with a GLP-1 receptor antagonist was performed to determine the contribution of GLP-1 to acute regulation of food intake.

We found that ACSL5IKO mice experienced rapid and sustained protection from body weight and fat mass accumulation during HFD feeding. While intestine specific deficiency of ACSL5 delayed gastric emptying and reduced dietary fat secretion, it did not result in increased excretion of dietary lipid in feces. Energy expenditure and physical activity were not increased in ACSL5IKO mice. Mice deficient in intestinal ACSL5 display significantly reduced energy intake during HFD, but not chow feeding. When HFD intake of control mice was matched to ACSL5IKO during pair-feeding studies, no differences in body weight or fat mass gain were observed between groups. Postprandial GLP-1 and PYY were significantly elevated in ACSL5IKO mice secondary to increased FA content in the distal small intestine. Blockade of GLP-1 signaling by administration of a long-acting GLP-1 receptor antagonist partially restored HFD intake of ACSL5IKO.

These data indicate that intestinal ACSL5 serves as a critical regulator of energy balance, protecting mice from diet-induced obesity exclusively by increasing satiety and reducing food intake during HFD feeding. The reduction in food intake observed in ACSL5IKO mice is driven, in part, by increased postprandial GLP-1 and PYY secretion. These effects are only observed during HFD feeding, suggesting that altered processing of dietary fat following intestinal ACSL5 ablation contributes to GLP-1 and PYY mediated increases in satiety.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem. However, no effective treatments are currently available. Thus, there is a critical need to develop novel drugs that can prevent and treat NAFLD with few side effects. In this study, Tussilagone (TUS), a natural sesquiterpene isolated from Tussilago farfara L, was explored in vitro and in vivo for its potential to treat NAFLD. Our results showed that in vitro TUS reduced oleic acid palmitate acid-induced triglyceride and cholesterol synthesis in HepG2cells, reduced intracellular lipid droplet accumulation, improved glucose metabolism disorders and increased energy metabolism and reduced oxidative stress levels. In vivo, TUS significantly reduced fat accumulation and improved liver injury in high-fat diet (HFD)-induced mice. TUS treatment significantly increased liver mitochondrial counts and antioxidant levels compared to the HFD group of mice. In addition, TUS was found to reduce the expression of genes involved in lipid synthesis sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FASN), and stearoy-CoA desaturase 1 (SCD1) in vitro and in vivo. Our results suggest that TUS may be helpful in the treatment of NAFLD, suggesting that TUS is a promising compound for the treatment of NAFLD. Our findings provided novel insights into the application of TUS in regulating lipid metabolism.

Lipid accumulation in adipocytes occurs through multifactorial effects such as overnutrition due to unbalanced eating habits, reduced physical activity, and genetic factors. In addition, obesity can be intensified by the dis-regulation of various metabolic systems such as differentiation, lipogenesis, lipolysis, and energy metabolism of adipocytes. In this study, the Jeju roasted peel extract from Citrus unshiu S.Markov. (JRC), which is discarded as opposed to the pulp of C. unshiu S.Markov., is commonly consumed to ameliorate obesity. To investigate the anti-obesity effect of JRC, these studies were conducted on differentiated 3T3-L1 cells and in high-fat diet-induced mice, and related methods were used to confirm whether it decreased lipid accumulation in adipocytes. The mechanism of inhibiting obesity by JRC was confirmed through mRNA expression studies. JRC suppressed lipid accumulation in adipocytes and adipose tissue, and significantly improved enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase and serum lipid profiles. In addition, it effectively modulated the expression of genes related to lipid and energy metabolism in adipose tissue. As a result, these findings suggest that JRC could be a therapeutic regulator of body fat accumulation by significantly alleviating the dis-regulation of intracellular lipid metabolism in adipocytes and by enhancement of energy metabolism (Approval No. CNU IACUC-YB-2023-98).

Di(2-ethylhexyl)phthalate (DEHP) is commonly used to increase the flexibility of plastics. In our previous study, DEHP may increase hepatic lipid accumulation through modulating of acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) expression. Nevertheless, it is hard to understand the association between DEHP and DGAT1 in the liver because only one dosage of DEHP was used. Thus, this study performed to investigate the role of DGAT1 on hepatic lipid metabolism after various dosages of DEHP exposure. Four-week-old male Sprague-Dawley rats (n = 5/group) were administered corn oil (vehicle) or DEHP (0.75, 7.5, 15, or 150 mg/kg/day) once daily for seven days. DEHP 150 mg/kg/day treated group increased body weight gain and relative liver weight compared to the control (P = 0.044 and P = 0.049, respectively). In histological observation, elevation of hepatic lipid accumulation was observed in all DEHP-treated groups, except DEHP 150 mg/kg/day, compared to that in the control (all P < 0.001). Portal inflammatory infiltration and acidophilic bodies were observed in the liver at DEHP 7.5 mg/kg/day and above treated groups. In addition, malondiadehyde levels, a marker of lipid peroxidation, in the liver were increased in DEHP 7.5, 15 and 150 mg/kg/day compared to the control (P = 0.017, P = 0.001, and P = 0.002, respectively). The expression of Dgat1 in the liver was significantly increased in DEHP 7.5, 15 and 150 mg/kg/day compared to the control group (P = 0.019, P = 0.002, and P < 0.001, respectively); however, there were no significant changes in the protein levels. Therefore, excessive oxidative stress caused by DEHP may induce liver damage such as inflammation rather than hepatic lipid accumulation by regulating DGAT1 transcription.

Acyltransferase enzymes (EC 2.3.) are a large group of enzymes that transfer acyl groups to a variety of substrates. This review focuses on fatty acyltransferases involved in the biosynthetic pathways of glycerolipids and sphingolipids and how these enzymes have been pharmacologically targeted in their biologic context. Glycerolipids and sphingolipids, commonly treated independently in their regulation and biologic functions, are put together to emphasize the parallelism in their metabolism and bioactive roles. Furthermore, a newly considered signaling molecule, 1-O-acylceramide, resulting from the acylation of ceramide by DGAT2 enzyme, is discussed. Finally, the implications of DGAT2 as a putative ceramide acyltransferase (CAT) enzyme, with a putative dual role in TAG and 1-O-acylceramide generation, are explored. SIGNIFICANCE STATEMENT: This manuscript reviews the current status of drug development in lipid acyltransferases. These are current targets in metabolic syndrome and other diseases, including cancer. A novel function for a member in this group of lipids has been recently reported in cancer cells. The responsible enzyme and biological implications of this added member are discussed.

Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known.

Experimental sepsis was induced by CLP (caecal ligation and puncture) in mice. Markers of hepatic steatosis, liver injury, hepatic oxidative stress, and inflammation were analysed using a combination of functional, imaging, lipidomic, protein expression and immune-enzymatic assays. To prevent LD formation, mice were treated orally with A922500, a pharmacological inhibitor of DGAT1.

We identified that liver LD overload correlates with liver injury and sepsis severity. Moreover, the progression of steatosis from 24 h to 48 h post-CLP occurs in parallel with increased cytokine expression, inflammatory cell recruitment and oxidative stress. Lipidomic analysis of purified LDs demonstrated that sepsis leads LDs to harbour increased amounts of unsaturated fatty acids, mostly 18:1 and 18:2. An increased content of lipoperoxides within LDs was also observed. Conversely, the impairment of LD formation by inhibition of the DGAT1 enzyme reduces levels of hepatic inflammation and lipid peroxidation markers and ameliorates sepsis-induced liver injury.

Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis.

Sepsis is a complex life-threatening syndrome caused by dysregulated inflammatory and metabolic host responses to infection. The observation that lipid droplets may contribute to sepsis-associated organ injury by amplifying lipid peroxidation and inflammation provides a rationale for therapeutically targeting lipid droplets and lipid metabolism in sepsis.

Temperature affects a variety of cellular processes because the molecular motion of cellular constituents and the rate of biochemical reactions are sensitive to temperature changes. Thus, the adaptation to temperature is necessary to maintain cellular functions during temperature fluctuation, particularly in poikilothermic organisms. For a wide range of organisms, cellular lipid molecules play a pivotal role during thermal adaptation. Temperature changes affect the physicochemical properties of lipid molecules, resulting in the alteration of cell membrane-related functions and energy metabolism. Since the chemical structures of lipid molecules determine their physicochemical properties and cellular functions, cellular lipids, particularly fatty acid-containing lipid molecules, are remodeled as a thermal adaptation response to compensate for the effects of temperature change. In this chapter, we first introduce the structure and biosynthetic pathway of fatty acid-containing lipid molecules, such as phospholipid and triacylglycerol, followed by a description of the cellular lipid-mediated mechanisms of thermal adaptation and thermoregulatory behavior in animals.

The 1-acylglycerol-3-phosphate acyltransferase (AGPAT) acts as a crucial enzyme in the process of triacylglycerol (TAG) synthesis, enabling the acylation of lysophosphatidic acid (LPA) into phosphatidic acid (PA). In order to decode the distinctive roles of AGPAT isoforms in the TAG production pathway, three AGPAT isoforms were detected for the first time in the Chinese mitten crab Eriocheir sinensis (Es-agpat2, Es-agpat3, and Es-agpat4). The mRNA levels of Es-agpat2 and Es-agpat4 demonstrated a conspicuous presence in the hepatopancreas, with subsequent high levels in the heart, muscle, and thoracic ganglion. On the other hand, the thoracic ganglion exhibited abundant levels of Es-agpat3, while other tissues recorded relatively low expression levels. Observing the molting cycle of E. sinensis, the hepatopancreas showed minimum expression levels of Es-agpat2 and Es-agpat4 at stage A/B. A peak at stage C was noted, which was then followed by a gradual drop until stage E. For the ovarian development cycle, stage II witnessed the maximum expression level of Es-agpat2 and Es-agpat4, succeeded by a sharp fall in stage III. After this, there was an increasing trend from stage III up to stage V. Expression of Es-agpat3 in the hepatopancreas was consistently lower than Es-agpat2 and Es-agpat4 during either the molting or ovarian development. However, in terms of ovarian expression, Es-agpat3 outperformed Es-agpat2 and Es-agpat4. It exhibited a steep increase in expression, peaking at stage II and subsequently diminishing. In situ hybridization (ISH) revealed that in stages II and IV hepatopancreas, Es-agpat4-mRNA was primarily located in fibrillar cells (F cell) and resorptive cells (R cell), with no signal from Es-agpat3. During stage II of ovarian development, both Es-agpat3-mRNA and Es-agpat4-mRNA were located in the cytoplasm of previtellogenic oocyte (PRO) and endogenous vitellogenic oocyte (EN), with no expression at stage IV. Additionally, the silencing of Es-agpat2 and Es-agpat4 caused a downward trend in the expression levels of all subsequent genes in the E. sinensis TAG synthesis pathway. To sum up, these findings suggest that the three Es-agpats may have unique functions in TAG synthesis during either the molting process or ovarian maturation of E. sinensis.

Acyl-coenzyme A (CoA):diacylglycerol acyltransferase 2 (DGAT2) catalyzes the last stage of triacylglycerol (TAG) synthesis, a process that forms ester bonds with diacylglycerols (DAG) and fatty acyl-CoA substrates. The enzymatic role of Dgat2 has been studied in various biological species. Still, the full description of how Dgat2 channels fatty acids in skeletal myocytes and the consequence thereof in glucose uptake have yet to be well established. Therefore, this study explored the mediating role of Dgat2 in glucose uptake and fatty acid partitioning under short interfering ribonucleic acid (siRNA)-mediated Dgat2 knockdown conditions. Cells transfected with Dgat2 siRNA downregulated glucose transporter type 4 (Glut4) messenger RNA (mRNA) expression and decreased the cellular uptake of [1-14C]-labeled 2-deoxyglucose up to 24.3% (p < 0.05). Suppression of Dgat2 deteriorated insulininduced Akt phosphorylation. Dgat2 siRNA reduced [1-14C]-labeled oleic acid incorporation into TAG, but increased the level of [1-14C]-labeled free fatty acids at 3 h after initial fatty acid loading. In an experiment of chasing radioisotope-labeled fatty acids, Dgat2 suppression augmented the level of cellular free fatty acids. It decreased the level of re-esterification of free fatty acids to TAG by 67.6% during the chase period, and the remaining pulses of phospholipids and cholesteryl esters were decreased by 34.5% and 61%, respectively. Incorporating labeled fatty acids into beta-oxidation products increased in Dgat2 siRNA transfected cells without gene expression involving fatty acid oxidation. These results indicate that Dgat2 has regulatory function in glucose uptake, possibly through the reaction of TAG with endogenously released or recycled fatty acids.

Introduction: Human milk delivers critical nutritional and immunological support to human infants. Milk fat globules (MFGs) and their associated membranes (MFGMs) contain the majority of milk lipids and many bioactive components that contribute to neonatal development and health, yet their compositions have not been fully defined, and the mechanisms responsible for formation of these structures remain incompletely understood. Methods: In this study, we used untargeted mass spectrometry to quantitatively profile the protein compositions of freshly obtained MFGs and their paired, physically separated MFGM fractions from 13 human milk samples. We also quantitatively profiled the MFG protein compositions of 9 pooled milk samples from 18 lactating mouse dams. Results: We identified 2,453 proteins and 2,795 proteins in the majority of human MFG and MFGM samples, respectively, and 1,577 proteins in mouse MFGs. Using paired analyses of protein abundance in MFGMs compared to MFGs (MFGM-MFG; 1% FDR), we identified 699 proteins that were more highly abundant in MFGMs (MFGM-enriched), and 201 proteins that were less abundant in MFGMs (cytoplasmic). MFGM-enriched proteins comprised membrane systems (apical plasma membrane and multiple vesicular membranes) hypothesized to be responsible for lipid and protein secretion and components of membrane transport and signaling systems. Cytoplasmic proteins included ribosomal and proteasomal systems. Comparing abundance between human and mouse MFGs, we found a positive correlation (R 2 = 0.44, p < 0.0001) in the relative abundances of 1,279 proteins that were found in common across species. Discussion: Comparative pathway enrichment analyses between human and mouse samples reveal similarities in membrane trafficking and signaling pathways involved in milk fat secretion and identify potentially novel immunological components of MFGs. Our results advance knowledge of the composition and relative quantities of proteins in human and mouse MFGs in greater detail, provide a quantitative profile of specifically enriched human MFGM proteins, and identify core cellular systems involved in milk lipid secretion.

Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

Two distinct diacylglycerol acyltransferases (DGAT1 and DGAT2) catalyze the final committed step of triacylglycerol (TG) synthesis in hepatocytes. After its synthesis in the endoplasmic reticulum (ER) TG is either stored in cytosolic lipid droplets (LDs) or is assembled into very low-density lipoproteins in the ER lumen. TG stored in cytosolic LDs is hydrolyzed by adipose triglyceride lipase (ATGL) and the released fatty acids are converted to energy by oxidation in mitochondria. We hypothesized that targeting/association of ATGL to LDs would differ depending on whether the TG stores were generated through DGAT1 or DGAT2 activities. Individual inhibition of DGAT1 or DGAT2 in Huh7 hepatocytes incubated with oleic acid did not yield differences in TG accretion while combined inhibition of both DGATs completely prevented TG synthesis suggesting that either DGAT can efficiently esterify exogenously supplied fatty acid. DGAT2-made TG was stored in larger LDs, whereas TG formed by DGAT1 accumulated in smaller LDs. Inactivation of DGAT1 or DGAT2 did not alter expression (mRNA or protein) of ATGL, the ATGL activator ABHD5/CGI-58, or LD coat proteins PLIN2 or PLIN5, but inactivation of both DGATs increased PLIN2 abundance despite a dramatic reduction in the number of LDs. ATGL was found to preferentially target to LDs generated by DGAT1 and fatty acids released from TG in these LDs were also preferentially used for fatty acid oxidation. Combined inhibition of DGAT2 and ATGL resulted in larger LDs, suggesting that the smaller size of DGAT1-generated LDs is the result of increased lipolysis of TG in these LDs.

Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.

Regulation of diacylglycerol acyltransferase (DGAT) and pancreatic lipase (PL) activities is important in the treatment of triacylglycerol (TG)-related metabolic diseases. Garcinia mangostana, also known as mangosteen, is a traditional medicine ingredient used in the treatment of inflammation in Southeast Asia. In this study, The ethanolic extract of G. mangostana peel inhibited human recombinant DGAT1 and DGAT2, and PL enzyme activities in vitro. The inhibitory activity of DGAT1 and DGAT2 enzymes of four representative bioactive substances in mangosteen was confirmed. In addition, G. mangostana was confirmed to suppress the serum TG levels in C57 mice by inhibiting the absorption and synthesis of TG in the gastrointestinal tract. Through this study, it was revealed that G. mangostana extract could be useful for the prevention and amelioration of TG-related metabolic diseases such as obesity and fatty liver.

The antiobesity effects of kimchi with catechin and lactic acid bacteria as starters were studied in C57BL/6 mice with high-fat diet (HFD)-induced obesity. We prepared four types of kimchi: commercial kimchi, standard kimchi, green tea functional kimchi, and catechin functional kimchi (CFK). Body weight and weight of adipose tissue were significantly lower in the kimchi-treated groups than in the HFD and Salt (HFD +1.5% NaCl) groups. In addition, in the CFK group, the serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol were significantly lower and those of high-density lipoprotein cholesterol were markedly higher than the corresponding levels in the HFD and Salt groups. Moreover, CFK reduced fat cells and crown-like structures in the liver and epididymal fat tissues. The protein expression of adipo/lipogenesis-related genes in the liver and epididymal fat tissues was significantly lower (1.90-7.48-fold) in the CFK group than in the HFD and Salt groups, concurrent with upregulation of lipolysis-related genes (1.71-3.38-fold) and downregulation of inflammation-related genes (3.17-5.06-fold) in epididymal fat tissues. In addition, CFK modulated the gut microbiomes of obese mice by increasing the abundance of Bacteroidetes (7.61%), while in contrast, Firmicutes (82.21%) decreased. In addition, the presence of the Erysipelotrichaceae (8.37%) family in the CFK group decreased, while the number of beneficial bacteria of the families, Akkermansiaceae (6.74%), Lachnospiraceae (14.95%), and Lactobacillaceae (38.41%), increased. Thus, CFK exhibited an antiobesity effect through its modulation of lipid metabolism and the microbiome.

Triacylglycerol (TGA) is the primary component of intramuscular fat. Expression of diacylglyceryl transferase (DGAT) determines the polyester differentiation ability of precursor adipocytes. The two DGAT isoforms (DGAT1 and DGAT2) play different roles in TAG metabolism. This study investigates the roles of DGAT1 and DGAT2 in signaling pathways related to differentiation and lipid metabolism in Yanbian bovine preadipocytes. sh-DGAT1 (sh-1), sh-DGAT2 (sh-2), and sh-DGAT1 + sh-DGAT2 (sh-1 + 2) were prepared using short interfering RNA (siRNA) interference technique targeting DGAT1 and DGAT2 genes and infected bovine preadipocytes. Molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, were used to investigate the effects on the differentiation of Yanbian bovine preadipocytes. After interference with DGAT1 and DGAT2 genes, the contents of TAG and adiponectin were decreased. The TAG content in the sh-2 and sh-1 + 2 groups was significantly lower than that in the sh-NC group. RNA sequencing (RNA-seq) results showed 2070, 2242, and 2446 DEGs in the sh-1, sh-2, and sh-1 + 2 groups, respectively. The DEGs of the sh-2 group were mainly concentrated in the PPAR, AMPK, and Wnt signaling pathways associated with adipocyte proliferation and differentiation. These results demonstrated that at the mRNA level, DGAT2 plays a more important role in lipid metabolism than DGAT1.

Acylation modifications play a central role in biological and physiological processes. Across a range of biomolecules from phospholipids to triglycerides to proteins, introduction of a hydrophobic acyl chain can dramatically alter the biological function and cellular localization of these substrates. Amongst the enzymes catalyzing these modifications, the membrane bound O-acyltransferase (MBOAT) family occupies an intriguing position as the combined substrate selectivities of the various family members span all three classes of these biomolecules. MBOAT-dependent substrates are linked to a wide range of health conditions including metabolic disease, cancer, and neurodegenerative disease. Like many integral membrane proteins, these enzymes have presented challenges to investigation due to their intractability to solubilization and purification. However, over the last several years new solubilization approaches coupled with computational modeling, crystallography, and cryoelectron microscopy have brought an explosion of structural information for multiple MBOAT family members. These studies enable comparison of MBOAT structure and function across members catalyzing modifications of all three substrate classes, revealing both conserved features amongst all MBOATs and distinct architectural features that correlate with different acylation substrates ranging from lipids to proteins. We discuss the methods that led to this renaissance of MBOAT structural investigations, our new understanding of MBOAT structure and implications for catalytic function, and the potential impact of these studies for development of new therapeutics targeting MBOAT-dependent physiological processes.

Obesity results from the expansion of adipose tissue, a versatile tissue regulating energy homeostasis, adipokine secretion, thermogenesis, and inflammation. The primary function of adipocytes is thought to be lipid storage through lipid synthesis, which is presumably intertwined with adipogenesis. However, during prolonged fasting, adipocytes are depleted of lipid droplets yet retain endocrine function and an instant response to nutrients. This observation led us to question whether lipid synthesis and storage can be uncoupled from adipogenesis and adipocyte function. By inhibiting key enzymes in the lipid synthesis pathway during adipocyte development, we demonstrated that a basal level of lipid synthesis is essential for adipogenesis initiation but not for maturation and maintenance of adipocyte identity. Furthermore, inducing dedifferentiation of mature adipocytes abrogated adipocyte identity but not lipid storage. These findings suggest that lipid synthesis and storage are not the defining features of adipocytes and raise the possibility of uncoupling lipid synthesis from adipocyte development to achieve smaller and healthier adipocytes for the treatment of obesity and related disorders.

Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.

Nanoplastics are common contaminants in the living environment. Thus far, no investigations have focused on small intestinal injury in the offspring of adult mice that were exposed to nanoplastics through the respiratory system during pregnancy. Here, we evaluated potential intestinal injury in the offspring of adult mice that were subjected to maternal 80 nm polystyrene nanoparticle (PS-NP) exposure during gestation. PS-NP exposure significantly reduced the birth weight of female mice compared with male mice. However, the adult body weights of the female and male offspring were substantially greater in the PS-NP-exposed groups. Additionally, we found that exposure to PS-NPs during pregnancy caused histological changes in the small intestines of both female and male offspring. Mechanistic analysis revealed upregulation of reactive oxygen species in the small intestines, as indicated by changes in the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Furthermore, exposure to PS-NPs led to downregulation of GPx4, FTH1, and FTL protein levels, indicating initiation of ferroptosis. Notably, the changes in mRNA expression levels of GPx4, FTH1, and FTL differed between female and male offspring. Although all phenotypes failed to demonstrate classic dose-dependent effects, the data imply that small intestinal toxicity is greater in female offspring than in male offspring. Our results suggest that PS-NP exposure during pregnancy causes sex-specific small intestinal toxicity, which might contribute to reactive oxygen species activation and subsequent ferroptosis. Overall, this study showed toxic effects in offspring after PS-NP exposure during pregnancy.

Duckweeds are amongst the fastest growing of higher plants, making them attractive high-biomass targets for biofuel feedstock production. Their fronds have high rates of fatty acid synthesis to meet the demand for new membranes, but triacylglycerols (TAG) only accumulate to very low levels. Here we report on the engineering of Lemna japonica for the synthesis and accumulation of TAG in its fronds. This was achieved by expression of an estradiol-inducible cyan fluorescent protein-Arabidopsis WRINKLED1 fusion protein (CFP-AtWRI1), strong constitutive expression of a mouse diacylglycerol:acyl-CoA acyltransferase2 (MmDGAT), and a sesame oleosin variant (SiOLE(*)). Individual expression of each gene increased TAG accumulation by 1- to 7-fold relative to controls, while expression of pairs of these genes increased TAG by 7- to 45-fold. In uninduced transgenics containing all three genes, TAG accumulation increased by 45-fold to 3.6% of dry weight (DW) without severely impacting growth, and by 108-fold to 8.7% of DW after incubation on medium containing 100 μm estradiol for 4 days. TAG accumulation was accompanied by an increase in total fatty acids of up to three-fold to approximately 15% of DW. Lipid droplets from fronds of all transgenic lines were visible by confocal microscopy of BODIPY-stained fronds. At a conservative 12 tonnes (dry matter) per acre and 10% (DW) TAG, duckweed could produce 350 gallons of oil/acre/year, approximately seven-fold the yield of soybean, and similar to that of oil palm. These findings provide the foundation for optimizing TAG accumulation in duckweed and present a new opportunity for producing biofuels and lipidic bioproducts.

Pregnancy toxemia is a nutritional metabolic disease during late gestation in small ruminants. The condition is characterized by disorders in carbohydrate and fat metabolism. Obese and multiparous ewes are particularly susceptible to pregnancy toxemia, which may lead to maternal death, abortion, or premature birth. Highly productive multiparous meat ewes are major breeding animals, which has led to an increased incidence of the disease. However, the pathogenesis of pregnancy toxemia remains unclear and adequate disease prevention and treatment strategies are absent. Investigating the pathogenesis of pregnancy toxemia, especially the metabolic pathways of hepatic lipids, is key to an improved understanding of the condition. This review provides a snapshot of the genes that are associated with lipid metabolism in the ovine liver, including genes involved in fatty acid oxidation, acetyl coenzyme metabolism, and triglyceride synthesis; describes the interrelationships between these genes; and summarizes the diagnosis, prevention, and treatment of pregnancy toxemia.

In higher plants, acyl-CoA:diacylglycerol acyltransferase (DGAT) and phospholipid:diacylglycerol acyltransferase (PDAT) catalyze the terminal step of triacylglycerol (TAG) synthesis in acyl-CoA-dependent and -independent pathways, respectively. Avocado (Persea americana) mesocarp, a nonseed tissue, accumulates significant amounts of TAG (~70% by dry weight) that is rich in heart-healthy oleic acid (18:1). The oil accumulation stages of avocado mesocarp development coincide with high expression levels for type-1 DGAT (DGAT1) and PDAT1, although type-2 DGAT (DGAT2) expression remains low. The strong preference for oleic acid demonstrated by the avocado mesocarp TAG biosynthetic machinery represents lucrative biotechnological opportunities, yet functional characterization of these three acyltransferases has not been explored to date. We expressed avocado PaDGAT1, PaDGAT2, and PaPDAT1 in bakers' yeast and leaves of Nicotiana benthamiana. PaDGAT1 complemented the TAG biosynthesis deficiency in the quadruple mutant yeast strain H1246, and substantially elevated total cellular lipid content. In vitro enzyme assays showed that PaDGAT1 prefers oleic acid compared to palmitic acid (16:0). Both PaDGAT1 and PaPDAT1 increased the lipid content and elevated oleic acid levels when expressed independently or together, transiently in N. benthamiana leaves. These results indicate that PaDGAT1 and PaPDAT1 prefer oleate-containing substrates, and their coordinated expression likely contributes to sustained TAG synthesis that is enriched in oleic acid. This study establishes a knowledge base for future metabolic engineering studies focused on exploitation of the biochemical properties of PaDGAT1 and PaPDAT1.

Bile reflux plays a key role in the development of gastric intestinal metaplasia (GIM), an independent risk factor of gastric cancer. Here, we aimed to explore the biological mechanism of GIM induced by bile reflux in a rat model.

Rats were treated with 2% sodium salicylate and allowed to freely drink 20 mmol/L sodium deoxycholate for 12 weeks, and GIM was confirmed by histopathological analysis. Gastric microbiota was profiled according to the 16S rDNA V3-V4 region, gastric transcriptome was sequenced, and serum bile acids (BAs) were analyzed by targeted metabolomics. Spearman's correlation analysis was used in constructing the network among gastric microbiota, serum BAs, and gene profiles. Real-time polymerase chain reaction (RT-PCR) measured the expression levels of nine genes in the gastric transcriptome.

In the stomach, deoxycholic acid (DCA) decreased the microbial diversity but promoted the abundances of several bacterial genera, such as Limosilactobacillus, Burkholderia-Caballeronia-Paraburkholderia, and Rikenellaceae RC9 gut group. Gastric transcriptome showed that the genes enriched in gastric acid secretion were significantly downregulated, whereas the genes enriched in fat digestion and absorption were obviously upregulated in GIM rats. The GIM rats had four promoted serum BAs, namely cholic acid (CA), DCA, taurocholic acid, and taurodeoxycholic acid. Further correlation analysis showed that the Rikenellaceae RC9 gut group was significantly positively correlated with DCA and RGD1311575 (capping protein-inhibiting regulator of actin dynamics), and RGD1311575 was positively correlated with Fabp1 (fatty acid-binding protein, liver), a key gene involved in fat digestion and absorption. Finally, the upregulated expression of Dgat1 (diacylglycerol acyltransferase 1) and Fabp1 related to fat digestion and absorption was identified by RT-PCR and IHC.

DCA-induced GIM enhanced gastric fat digestion and absorption function and impaired gastric acid secretion function. The DCA-Rikenellaceae RC9 gut group-RGD1311575/Fabp1 axis might play a key role in the mechanism of bile reflux-related GIM.

Humans are exposed to different kinds of environmental contaminants or drugs throughout their lifetimes. The widespread presence of these compounds has raised concerns about the consequent adverse effects on lactating women. The constitutive androstane receptor (CAR, Nr1i3) is known as a xenobiotic sensor for environmental pollution or drugs. In this study, the model environmental chemical 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene, TCPOBOP (TC), which is a highly specific agonist of CAR, was used to investigate the effects of exogenous exposure on lactation function and offspring health in mice. The results revealed that TC exposure decreased the proliferation of mammary epithelial cells during pregnancy. This deficiency further compromised lobular-alveolar structures, resulting in alveolar cell apoptosis, as well as premature stoppage of the lactation cycle and aberrant lactation. Furthermore, TC exposure significantly altered the size and number of milk lipid droplets, suggesting that TC exposure inhibits milk lipid synthesis. Additionally, TC exposure interfered with the milk lipid metabolism network, resulting in the inability of TC-exposed mice to efficiently secrete nutrients and feed their offspring. These findings demonstrated that restricted synthesis and secretion of milk lipids would indirectly block mammary gland form and function, which explained the possible reasons for lactation failure and retarded offspring growth.

Dysregulation of lipid metabolism is associated with obesity and metabolic diseases but there is also increasing evidence of a relationship between lipid body excess and cancer. Lipid body synthesis requires diacylglycerol acyltransferases (DGATs) which catalyze the last step of triacylglycerol synthesis from diacylglycerol and acyl-coenzyme A. The DGATs and in particular DGAT2, are therefore considered potential therapeutic targets for the control of these pathologies. Here, the murine and the human DGAT2 were overexpressed in the oleaginous yeast Yarrowia lipolytica deleted for all DGAT activities, to evaluate the functionality of the enzymes in this heterologous host and DGAT activity inhibitors. This work provides evidence that mammalian DGATs expressed in Y. lipolytica are a useful tool for screening chemical libraries to identify potential inhibitors or activators of these enzymes of therapeutic interest.

Excess plasma lipid levels are a risk factor for various cardiometabolic disorders. Studies have shown that improving dyslipidemia lowers the progression of these disorders. In this study, we investigated the role of ATP-binding cassette transporter C10 (ABCC10) in regulating lipid metabolism. Our data indicate that deletion of the Abcc10 gene in male mice results in lower plasma and intestinal triglycerides by around 38% and 36%, respectively. Furthermore, deletion of ABCC10 ameliorates diet-induced obesity in mice and leads to a better response during insulin and glucose tolerance tests. Unexpectedly, ABCC10 deficiency does not affect triglyceride levels or atherosclerosis in ApoE-deficient mice. In addition, our studies demonstrate low oleate uptake by enterocytes (~25-30%) and less absorption (~37%) of triglycerides in the small intestine of ABCC10 knockout mice. Deletion of the Abcc10 gene also alters several lipid metabolism genes in the intestine, suggesting that ABCC10 regulates dietary fat absorption, which may contribute to diet-induced obesity in mice.