The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity.

Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.

High-performance fibre battery with polymer gel electrolyte.

Replacement of liquid electrolytes with polymer gel electrolytes is recognized as a general and effective way of solving safety problems and achieving high flexibility in wearable batteries1-6. However, the poor interface between polymer gel electrolyte and electrode, caused by insufficient wetting, produces much poorer electrochemical properties, especially during the deformation of the battery7-9. Here we report a strategy for designing channel structures in electrodes to incorporate polymer gel electrolytes and to form intimate and stable interfaces for high-performance wearable batteries. As a demonstration, multiple electrode fibres were rotated together to form aligned channels, while the surface of each electrode fibre was designed with networked channels. The monomer solution was effectively infiltrated first along the aligned channels and then into the networked channels. The monomers were then polymerized to produce a gel electrolyte and form intimate and stable interfaces with the electrodes. The resulting fibre lithium-ion battery (FLB) showed high electrochemical performances (for example, an energy density of about 128 Wh kg-1). This strategy also enabled the production of FLBs with a high rate of 3,600 m h-1 per winding unit. The continuous FLBs were woven into a 50 cm × 30 cm textile to provide an output capacity of 2,975 mAh. The FLB textiles worked safely under extreme conditions, such as temperatures of -40 °C and 80 °C and a vacuum of -0.08 MPa. The FLBs show promise for applications in firefighting and space exploration.

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8+ T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses. Antigen stimulation and inflammation induced SPTLC2 expression, and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress, and CD8+ T cell death. Protective CD8+ T cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore, SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T cell metabolic fitness.

Scalable production of high-performing woven lithium-ion fibre batteries.

Fibre lithium-ion batteries are attractive as flexible power solutions because they can be woven into textiles, offering a convenient way to power future wearable electronics1-4. However, they are difficult to produce in lengths of more than a few centimetres, and longer fibres were thought to have higher internal resistances3,5 that compromised electrochemical performance6,7. Here we show that the internal resistance of such fibres has a hyperbolic cotangent function relationship with fibre length, where it first decreases before levelling off as length increases. Systematic studies confirm that this unexpected result is true for different fibre batteries. We are able to produce metres of high-performing fibre lithium-ion batteries through an optimized scalable industrial process. Our mass-produced fibre batteries have an energy density of 85.69 watt hour per kilogram (typical values8 are less than 1 watt hour per kilogram), based on the total weight of a lithium cobalt oxide/graphite full battery, including packaging. Its capacity retention reaches 90.5% after 500 charge-discharge cycles and 93% at 1C rate (compared with 0.1C rate capacity), which is comparable to commercial batteries such as pouch cells. Over 80 per cent capacity can be maintained after bending the fibre for 100,000 cycles. We show that fibre lithium-ion batteries woven into safe and washable textiles by industrial rapier loom can wirelessly charge a cell phone or power a health management jacket integrated with fibre sensors and a textile display.

Large-area display textiles integrated with functional systems.

Displays are basic building blocks of modern electronics1,2. Integrating displays into textiles offers exciting opportunities for smart electronic textiles-the ultimate goal of wearable technology, poised to change the way in which we interact with electronic devices3-6. Display textiles serve to bridge human-machine interactions7-9, offering, for instance, a real-time communication tool for individuals with voice or speech difficulties. Electronic textiles capable of communicating10, sensing11,12 and supplying electricity13,14 have been reported previously. However, textiles with functional, large-area displays have not yet been achieved, because it is challenging to obtain small illuminating units that are both durable and easy to assemble over a wide area. Here we report a 6-metre-long, 25-centimetre-wide display textile containing 5 × 105 electroluminescent units spaced approximately 800 micrometres apart. Weaving conductive weft and luminescent warp fibres forms micrometre-scale electroluminescent units at the weft-warp contact points. The brightness between electroluminescent units deviates by less than 8 per cent and remains stable even when the textile is bent, stretched or pressed. Our display textile is flexible and breathable and withstands repeated machine-washing, making it suitable for practical applications. We show that an integrated textile system consisting of display, keyboard and power supply can serve as a communication tool, demonstrating the system's potential within the 'internet of things' in various areas, including healthcare. Our approach unifies the fabrication and function of electronic devices with textiles, and we expect that woven-fibre materials will shape the next generation of electronics.

Regulatory T cell-derived interleukin-15 promotes the diversity of immunological memory.

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1+ IL-7Rα- CD62L- terminal effector memory CD8+ T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8+ T cell pool. Our findings identify Treg cells as an essential IL-15 source maintaining tTEM cells and suggest that Treg cells promote the diversity of immunological memory.

CD8 agonism functionally activates memory T cells and enhances antitumor immunity.

Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody-mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell-mediated cytotoxicity and promoted effector cytokine production in a glucose- and glutamine-dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti-CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell-based cancer immunotherapy.

HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface.

HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4+ T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4+ T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4+ T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding-deficient Nef variant fails to impair CD4+ T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo.

Multicolor, Fluorescent Supercapacitor Fiber.

Fiber-shaped supercapacitors have attracted broad attentions from both academic and industrial communities due to the demonstrated potentials as next-generation power modules. However, it is important while remains challenging to develop dark-environment identifiable supercapacitor fibers for enhancement on operation convenience and security in nighttime applications. Herein, a novel family of colorful fluorescent supercapacitor fibers has been produced from aligned multi-walled carbon nanotube sheets. Fluorescent dye particles are introduced and stably anchored on the surfaces of aligned multi-walled carbon nanotubes to prepare hybrid fiber electrodes with a broad range of colors from red to purple. The fluorescent component in the dye introduces fluorescent indication capability to the fiber, which is particularly promising for flexible and wearable devices applied in dark environment. In addition, the colorful fluorescent supercapacitor fibers also maintain high electrochemical performance under cyclic bending and charge-discharge processes.

CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1.

UNLABELLED: The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol. CONCLUSION: These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders.

Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.

RATIONALE: The peptide ligand apelin and its receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system, including cardiovascular development in model organisms such as xenopus and zebrafish. OBJECTIVE: This study aimed to characterize the embryonic lethal phenotype of the Apj-/- mice and to define the involved downstream signaling targets. METHODS AND RESULTS: We report the first characterization of the embryonic lethality of the Apj-/- mice. More than half of the expected Apj-/- embryos died in utero because of cardiovascular developmental defects. Those succumbing to early embryonic death had markedly deformed vasculature of the yolk sac and the embryo, as well as poorly looped hearts with aberrantly formed right ventricles and defective atrioventricular cushion formation. Apj-/- embryos surviving to later stages demonstrated incomplete vascular maturation because of a deficiency of vascular smooth muscle cells and impaired myocardial trabeculation and ventricular wall development. The molecular mechanism implicates a novel, noncanonical signaling pathway downstream of apelin-APJ involving Gα13, which induces histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and cytoplasmic translocation, resulting in activation of myocyte enhancer factor 2. Apj-/- mice have greater endocardial Hdac4 and Hdac5 nuclear localization and reduced expression of the myocyte enhancer factor 2 (MEF2) transcriptional target Krüppel-like factor 2. We identify a number of commonly shared transcriptional targets among apelin-APJ, Gα13, and MEF2 in endothelial cells, which are significantly decreased in the Apj-/- embryos and endothelial cells. CONCLUSIONS: Our results demonstrate a novel role for apelin-APJ signaling as a potent regulator of endothelial MEF2 function in the developing cardiovascular system.

Essential role of Apelin signaling during lymphatic development in zebrafish.

OBJECTIVE: Apelin and its cognate receptor Aplnr/Apj are essential for diverse biological processes. However, the function of Apelin signaling in lymphatic development remains to be identified, despite the preferential expression of Apelin and Aplnr within developing blood and lymphatic endothelial cells in vertebrates. In this report, we aim to delineate the functions of Apelin signaling during lymphatic development. APPROACH AND RESULTS: We investigated the functions of Apelin signaling during lymphatic development using zebrafish embryos and found that attenuation of Apelin signaling substantially decreased the formation of the parachordal vessel and the number of lymphatic endothelial cells within the developing thoracic duct, indicating an essential role of Apelin signaling during the early phase of lymphatic development. Mechanistically, we found that abrogation of Apelin signaling selectively attenuates lymphatic endothelial serine-threonine kinase Akt 1/2 phosphorylation without affecting the phosphorylation status of extracellular signal-regulated kinase 1/2. Moreover, lymphatic abnormalities caused by the reduction of Apelin signaling were significantly exacerbated by the concomitant partial inhibition of serine-threonine kinase Akt/protein kinase B signaling. Apelin and vascular endothelial growth factor-C (VEGF-C) signaling provide a nonredundant activation of serine-threonine kinase Akt/protein kinase B during lymphatic development because overexpression of VEGF-C or apelin was unable to rescue the lymphatic defects caused by the lack of Apelin or VEGF-C, respectively. CONCLUSIONS: Taken together, our data present compelling evidence suggesting that Apelin signaling regulates lymphatic development by promoting serine-threonine kinase Akt/protein kinase B activity in a VEGF-C/VEGF receptor 3-independent manner during zebrafish embryogenesis.

[Roles of cytochrome c, caspase-9, and caspase-3 in pentavalent vanadium-induced neuronal apoptosis].

OBJECTIVE: To investigate the roles of cytochrome c (Cyt-c), caspase-9, and caspase-3 in pentavalent vanadium-induced neuronal apoptosis and to provide a basis for mechanism research. METHODS: Neurons from rats aged 1-3 days were cultured and treated with vanadium pentoxide (V2O5) at 5, 10, or 20 mmol/L. Neuronal apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling (TUNEL). The protein levels of Cyt-c, caspase-9, and caspase-3 were determined by Western blot. RESULTS: Apoptosis bodies were detected in the nuclei of neurons by TUNEL. The number of neurons with apoptosis bodies increased with increasing dose of V2O5 The apoptosis index (AI) was significantly higher in the 10 and 20 mm/L exposure groups than in the control group (P < 0.05 or P < 0.01). Western blot showed that the protein expression levels of Cyt-c and caspase-3 significantly increased in the 5 mmol/L exposure group as compared with the control group (P < 0.05). In the 10 and 20 mmol/L exposure groups, the protein expression of Cyt-c, caspase-9, and caspase-3 all increased as compared with the control group (P < 0.01). Neuronal AI was positively correlated with Cyt-c, caspase-9, and caspase-3 (r = 0.954, P < 0.01; r = 0.938, P < 0.01; r = 0.943, P < 0.01). CONCLUSION: Pentavalent vanadium may induce neuronal apoptosis. The protein expression of Cyt-c, caspase-9, and caspase-3 may play an important role in neuronal apoptosis induced by pentavalent vanadium.

Cellular metabolism regulates the differentiation and function of T-cell subsets.

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.

A high-throughput quantitative approach reveals more small RNA modifications in mouse liver and their correlation with diabetes.

Studies of RNA modification are usually focused on tRNA. However the modification of other small RNAs, including 5.8S rRNA, 5S rRNA, and small RNA sized at 10-60 nt, is still largely unknown. In this study, we established an efficient method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) to simultaneously identify and quantify more than 40 different types of nucleosides in small RNAs. With this method, we revealed 23 modified nucleosides of tRNA from mouse liver, and 6 of them were observed for the first time in eukaryotic tRNA. Moreover, 5 and 4 modified nucleosides were detected for the first time in eukaryotic 5.8S and 5S rRNA, respectively, and 22 modified nucleosides were identified in the small RNAs sized at 30-60 or 10-30 nt. Interestingly, two groups of 5S rRNA peaks were observed when analyzed by HPLC, and the abundance of modified nucleosides is significantly different between the two groups of peaks. Further studies show that multiple modifications in small RNA from diabetic mouse liver are significantly increased or decreased. Taken together, our data revealed more modified nucleosides in various small RNAs and showed the correlation of small RNA modifications with diabetes. These results provide new insights to the role of modifications of small RNAs in their stability, biological functions, and correlation with diseases.

[Expression of caspase-3, Bcl-2, and Bax in pentavalent vanadium-induced neuronal apoptosis].

OBJECTIVE: To investigate the expression of caspase-3, Bcl-2, and Bax in pentavalent vanadium-induced neuronal apoptosis and the neurotoxicity of pentavalent vanadium to in vitro cultured rat neurons. METHODS: Neurons from rats were cultured in vitro and treated with different concentrations of V2O5. Neuronal apoptosis was evaluated by TdT-mediated dUTP-biotin nick end labeling (TUNEL). The expression of caspase-3, Bcl-2, and Bax in neurons was measured by Western blot. The images collected by gel imaging system and scanner were analyzed. RESULTS: The TUNEL showed that compared with the control group, the middle- and high-dose exposure groups had significantly increased apoptosis index (AI) of neurons (P < 0.05 or P < 0.01). The Western blot showed that compared with the control group, the middle- and high-dose exposure groups had significantly increased expression of caspase-3 and Bax and significantly decreased expression of Bcl-2 (P <0.05 or P < 0.01). The AI of neurons was positively correlated with the expression of caspase-3 and Bax (r = 0.943, P < 0.01; r = 0.937, P < 0.01) and negatively correlated with the expression of Bcl-2 (r = -0.908, P < 0.01). CONCLUSION: Pentavalent vanadium may induce neuronal apoptosis, and the expression of caspase-3, Bcl-2, and Bax, which regulate apoptosis, plays an important role in the neuronal apoptosis induced by pentavalent vanadium.

Highly Reliable Textile-Type Memristor by Designing Aligned Nanochannels.

Information-processing devices are the core components of modern electronics. Integrating them into textiles is the indispensable demand for electronic textiles to form close-loop functional systems. Memristors with crossbar configuration are regarded as promising building blocks to design woven information-processing devices that seamlessly unify with textiles. However, the memristors always suffer from severe temporal and spatial variations due to the random growth of conductive filaments during filamentary switching processes. Here, inspired by the ion nanochannels across synaptic membranes, a highly reliable textile-type memristor made of Pt/CuZnS memristive fiber with aligned nanochannels, showing small set voltage variation (<5.6%) under ultralow set voltage (≈0.089 V), high on/off ratio (≈106 ), and low power consumption (0.1 nW), is reported. Experimental evidence indicate that nanochannels with abundant active S defects can anchor silver ions and confine their migrations to form orderly and efficient conductive filaments. Such memristive performances enable the resultant textile-type memristor array to have high device-to-device uniformity and process complex physiological data like brainwave signals with high recognition accuracy (95%). The textile-type memristor arrays are mechanically durable to withstand hundreds of bending and sliding deformations, and seamlessly unified with sensing, power-supplying, and displaying textiles/fibers to form all-textile integrated electronic systems for new generation human-machine interactions.

Liver Patt1 deficiency protects male mice from age-associated but not high-fat diet-induced hepatic steatosis.

Patt1 is a newly identified protein acetyltransferase that is highly expressed in liver. However, the role of Patt1 in liver is still unclear. We generated Patt1 liver-specific knockout (LKO) mice and mainly measured the effect of hepatic Patt1 deficiency on lipid metabolism. Hepatic Patt1 deficiency in male mice markedly decreases fat mass and dramatically alleviates age-associated accumulation of lipid droplets in liver. Moreover, hepatic Patt1 abrogation in male mice significantly reduces the liver triglyceride and free fatty acid levels, but it has no effect on liver cholesterol level, liver weight, and liver function. Consistently, primary cultured Patt1-deficient hepatocytes are resistant to palmitic acid-induced lipid accumulation, but hepatic Patt1 deficiency fails to protect male mice from high-fat diet-induced hepatic steatosis. Further studies show that hepatic Patt1 deficiency decreases fatty acid uptake, reduces lipid synthesis, and enhances fatty acid oxidation, which may contribute to the attenuated hepatic steatosis in Patt1 LKO mice. These results demonstrate that Patt1 plays an important role in hepatic lipid metabolism and have implications toward resolving age-associated hepatic steatosis.