Significant Lipid Accumulation Research Articles

Evaluating oleaginous yeasts for enhanced microbial lipid production using sweetwater as a sustainable feedstock

BackgroundYeasts exhibit promising potential for the microbial conversion of crude glycerol, owing to their versatility in delivering a wide range of value-added products, particularly lipids. Sweetwater, a methanol-free by-product of the fat splitting process, has emerged as a promising alternative feedstock for the microbial utilization of crude glycerol. To further optimize sweetwater utilization, we compared the growth and lipid production capabilities of 21 oleaginous yeast strains under different conditions with various glycerol concentrations, sweetwater types and pH.ResultsWe found that nutrient limitation and the unique carbon composition of sweetwater boosted significant lipid accumulation in several strains, in particular Rhodosporidium toruloides NRRL Y-6987. Subsequently, to decipher the underlying mechanism, the transcriptomic changes of R. toruloides NRRL Y-6987 were further analyzed, indicating potential sugars and oligopeptides in sweetwater supporting growth and lipid accumulation as well as exogenous fatty acid uptake leading to the enhanced lipid accumulation.ConclusionOur comparative study successfully demonstrated sweetwater as a cost-effective feedstock while identifying R. toluroides NRRL Y-6987 as a highly promising microbial oil producer. Furthermore, we also suggested potential sweetwater type and strain engineering targets that could potentially enhance microbial lipid production.Graphical abstract

D-Tetramethrin causes zebrafish hepatotoxicity by inducing oxidative stress and inhibiting cell proliferation

d-Tetramethrin is one of the main components of mosquito control products, and is widely used for the control of dengue fever and insecticide production. Due to its widespread use, d-tetramethrin is a ubiquitous environmental pollutant and poses potential risks to human health. However, the effects of d-tetramethrin on liver morphology and function are not clearly established. In this study, we used zebrafish as an animal model to analyze the acute and chronic effects of d-tetramethrin exposure on the liver. We exposed zebrafish larvae and adults to different concentrations of d-tetramethrin and examined the impact of d-tetramethrin on lipid and glycogen metabolism, cellular properties, oxidative stress, cell proliferation, and apoptosis in the liver. We also analyzed transcriptional changes in genes related to apoptosis, inflammation, and cell proliferation using qPCR. Zebrafish exposed to d-tetramethrin exhibited severe liver damage, as evidenced by the presence of vacuoles and nuclear distortion in liver cells. The liver area in zebrafish larvae of the treatment group was significantly smaller than that of the control group. Significant lipid accumulation and decreased glycogen levels were observed in the livers of both zebrafish larvae and adults exposed to d-tetramethrin. Furthermore, d-tetramethrin exposure induced apoptosis and inflammation in zebrafish embryos. Additionally, d-tetramethrin caused liver damage, metabolic dysfunction, and impaired liver function. These results suggest that d-tetramethrin induces liver toxicity in zebrafish, by inducing oxidative stress and inhibiting cell proliferation.

DOP88 Lipids drive myofibroblast activation and the epithelial-mesenchymal transition process in Crohn’s Disease

Abstract Background Fibrostenosis represents one of the major clinical complications of Crohn’s Disease (CD). However, the molecular mechanisms underlying intestinal fibrogenesis remain poorly understood and anti-fibrotic therapy has not yet been developed. Growing evidences supports that oxidative stress and the epithelial-mesenchymal transition (EMT) process contribute to the development and progression of fibrosis. Here, we assessed the role of lipids in fibrogenesis and whether mitochondria dysfunction can support fibrosis formation. Methods Spatial metabolomics analysis and adipophilin (ADFP) staining were performed on surgical specimens from fibrotic ileum and the surrounding region (healthy) derived from CD patients. Fibroblasts isolated from fibrotic and healthy ileum and human induced pluripotent stem cell-derived intestinal organoids (iHOs) were treated for 1-3 weeks with lipid mix (2%) and analyzed by RNA sequencing. Pathways significantly modulated were validated by RT-PCR, WB, FACS analysis, and proliferative, migratory and contraction assays, and mitochondrial functions by Seahorse analyzer. Results Spatial metabolomics revealed a significant accumulation of lipids characterized by very long-chain fatty acids in the fibrotic area compared to surrounding healthy regions, which was further confirmed by ADFP staining. RNA-seq analysis showed overlapping dysregulated pathways between healthy fibroblasts stimulated with lipids and fibrotic fibroblasts, in particular genes related to cell cycle, cytoskeletal reorganization, migration, contractility and cell metabolism (oxidative stress) which were further confirmed by functional assays. Among the genes related to oxidative stress, lipid stimulation significantly decreased NFE2L2 and promoted an increase in CPT1A, gene encoding for a fatty oxidation mediator. Moreover, lipid-stimulated fibroblasts showed a reduction in mitochondrial respiration, particularly basal and maximal respiration, and spare respiratory capacity by Seahorse analysis. On the other hand, long exposure of iHOs to lipids promoted the EMT process through the upregulation of TWIST, ZEB, VIM, and S100a4. Conclusion Lipid stimulation induced myofibroblast activation through oxidative stress and alteration of mitochondrial metabolism, and increased the expression of EMT transcription factors in intestinal epithelial cells (iHOs) that may support fibroblast-mediated pro-fibrotic activity. These data indicate that regulators of fatty acid oxidation involved in the fibrotic process may represent new potential targets for the treatment of fibrostenotic CD patients.

Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE-/- mice

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice’s aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused by NPs exposure.

Role of TFEB-autophagy lysosomal pathway in palmitic acid induced renal tubular epithelial cell injury

Lysosomal dysfunction and impaired autophagic flux are involved in the pathogenesis of lipotoxicity in the kidney. Here, we investigated the role of transcription factor EB (TFEB), a master regulator of autophagy-lysosomal pathway, in palmitic acid induced renal tubular epithelial cells injury. We examined lipid accumulation, autophagic flux, expression of Ps211-TFEB, and nuclear translocation of TFEB in HK-2 cells overloaded with palmitic acid (PA). By utilizing immunohistochemistry, we detected TFEB expression in renal biopsy tissues from patients with diabetic nephropathy and normal renal tissue adjacent to surgically removed renal carcinoma (controls), as well as kidney tissues from rat fed with high-fat diet (HFD) and low-fat diet (LFD). We found significant lipid accumulation, increased apoptosis, accompanied with elevated Ps211-TFEB, decreased nuclear TFEB, reduced lysosome biogenesis and insufficient autophagy in HK-2 cells treated with PA. Kidney tissues from patients with diabetic nephropathy had lower nuclear and total levels of TFEB than that in control kidney tissues. Level of renal nuclear TFEB in HFD rats was also lower than that in LFD rats. Exogenous overexpression of TFEB increased the nuclear TFEB level in HK-2 cells treated with PA, promoted lysosomal biogenesis, improved autophagic flux, reduced lipid accumulation and apoptosis. Our results collectively indicate that PA is a strong inducer for TFEB phosphorylation modification at ser211 accompanied with lower nuclear translocation of TFEB. Impairment of TFEB-mediated lysosomal biogenesis and function by palmitic acid may lead to insufficient autophagy and promote HK-2 cells injury.

Dietary Intake of Fructooligosaccharides Protects against Metabolic Derangements Evoked by Chronic Exposure to Fructose or Galactose in Rats.

Diets rich in fat and sugars evoke chronic low-grade inflammation, leading to metabolic derangements. This study investigates the impact of fructose and galactose, two commonly consumed simple sugars, on exacerbation of the harmful effects caused by high fat intake. Additionally, the potential efficacy of fructooligosaccharides (FOS), a fermentable dietary fiber, in counteracting these effects is examined. Male Sprague-Dawley rats (six/group) are fed 8 weeks as follows: control 5% fat diet (CNT), 20% fat diet (FAT), FAT+10% FOS diet (FAT+FOS), FAT+25% galactose diet (FAT+GAL), FAT+GAL+10% FOS diet (FAT+GAL+FOS), FAT+25% fructose diet (FAT+FRU), FAT+FRU+10% FOS diet (FAT+FRU+FOS). The dietary manipulations tested do not affect body weight gain, blood glucose, or markers of systemic inflammation whereas significant increases in plasma concentrations of triacylglycerols, cholesterol, aspartate aminotransferase, and alanine aminotrasferase are detected in both FAT+FRU and FAT+GAL compared to CNT. In the liver and skeletal muscle, both sugars induce significant accumulation of lipids and advanced glycation end-products (AGEs). FOS supplementation prevents these impairments. This study extends the understanding of the deleterious effects of a chronic intake of simple sugars and demonstrates the beneficial role of the prebiotic FOS in dampening the sugar-induced metabolic impairments by prevention of lipid and AGEs accumulation.

CO2 to green fuel converter: Photoautotrophic-cultivation of microalgae and its lipids conversion to biodiesel

This research focused on utilizing photoautotrophically-cultivated microalgae as efficient converters of CO2 into high-quality renewable biodiesel. This study investigated the feasibility of capturing CO2 from the atmosphere (0.04 % CO2) and simulating industrial sources (20–40 % CO2) for utilization as a simulated waste carbon source for the growth and biodiesel feedstock accumulation of three photoautotrophically-cultivated microalgae species, including Chlorella sp. AARL G049, Tetradesmus obliquus AARL G090, and Desmodesmus opoliensis AARL G085. The results demonstrated that all the tested microalgae are promising CO2-to-fuel converters due to their ability to efficiently convert CO2 into lipid-rich biomass, which can subsequently be processed into biodiesel. All three strains of microalgae displayed remarkable CO2 capture capabilities as well as significant biomass production and lipid accumulation, with the highest performance observed under a 20 % CO2 concentration. The microalgae demonstrated CO2 fixation rates ranging from 0.020 to 0.072 g-CO2/L/day, leading to significant improvements in both biomass productivity, which ranged from 0.011 to 0.040 g/L/day, and lipid accumulation, which ranged from 0.22 to 3.39 mg/L/day. Additionally, the lipid content varied between 5.04 % and 14.75 %. Interestingly, changes in CO2 concentration, ranging from 0.04 % to 40 %, significantly influenced the composition of fatty acids, leading to elevated levels of C16–C18 fatty acids. Nevertheless, these alterations had a minimal impact on the overall quality of biodiesel. The estimated fuel characteristics of the produced biodiesel complied with global specifications for biodiesel, providing better oxidative stability (≥6 h), high heating value (≥39 MJ/kg), and cetane number (≥47). Therefore, this study emphasizes sustainable CO2 capture and the potential of microalgae as a renewable source of economically viable biodiesel.

Metabolic characteristics of granulosa cell tumor: role of PPARγ signaling†.

Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator-activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator-activated receptor gamma as a potential driver for primary granulosa cell tumor growth.

Effect of continuous planting on Casuarina equisetifolia rhizosphere soil physicochemical indexes, microbial functional diversity and metabolites.

Continuous planting has a severe impact on the growth of Casuarina equisetifolia. In this study, the effects of three different long-term monocultures (one, two and three replanting) on the physicochemical indexes, microbial functional diversity, and soil metabolomics were analyzed in C. equisetifolia rhizosphere soil. The results showed that rhizosphere soil organic matter content, cation exchange capacity, total and available nitrogen, total and available phosphorus, and total and available potassium contents significantly decreased with the increasing number of continuous plantings. The evaluation of microbial functional diversity revealed a reduction in the number of soil microorganisms that rely on carbohydrates for carbon sources and an increase in soil microorganisms that used phenolic acid, carboxylic acid, fatty acid, and amines as carbon sources. Soil metabolomics analysis showed a significant decrease in soil carbohydrate content and a significant accumulation of autotoxic acid, amine, and lipid in the C. equisetifolia rhizosphere soil. Consequently, the growth of C. equisetifolia could hinder total nutrient content and their availability. Thus, valuable insights for managing the cultivation of C. equisetifolia and soil remediation were provided.

ASC/Caspase-1-activated endothelial cells pyroptosis is involved in vascular injury induced by arsenic combined with high-fat diet

Environmental arsenic (As) or high-fat diet (HFD) exposure alone are risk factors for the development of cardiovascular disease (CVDs). However, the effects and mechanisms of co-exposure to As and HFD on the cardiovascular system remain unclear. The current study aimed to investigate the combined effects of As and HFD on vascular injury and shed some light on the underlying mechanisms. The results showed that co-exposure to As and HFD resulted in a significant increase in serum lipid levels and significant lipid accumulation in the aorta of rats compared with exposure to As or HFD alone. Meanwhile, the combined exposure altered blood pressure and disrupted the morphological structure of the abdominal aorta in rats. Furthermore, As combined with HFD exposure upregulated the expression of vascular endothelial cells pyroptosis-related proteins (ASC, Pro-caspase-1, Caspase-1, IL-18, IL-1β), as well as the expression of vascular endothelial adhesion factors (VCAM-1 and ICAM-1). More importantly, we found that with increasing exposure time, vascular injury-related indicators were significantly higher in the combined exposure group compared with exposure to As or HFD alone, and the vascular injury was more severe in female rats compared with male rats. Taken together, these results suggested that the combination of As and HFD induced vascular endothelial cells pyroptosis through activation of the ASC/Caspase-1 pathway. Therefore, vascular endothelial cells pyroptosis may be a potential molecular mechanism for vascular injury induced by As combined with HFD exposure.

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling.

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling.

Lipid metabolic disturbance induced by triphenyl phosphate and hydroxy metabolite in HepG2 cells

Triphenyl phosphate (TPHP) has been widely used as flame retardants and been detected with increasing frequency in environment. TPHP can transform into mono-hydroxylated phosphate (OH-TPHP) and diester diphenyl phosphate (DPHP) through biotransformation. So far, information on the cytotoxicity and molecular regulatory mechanisms of TPHP metabolites are still limit. This study investigated the adverse effects of TPHP, OH-TPHP, and DPHP in HepG2 cells in terms of cell proliferation, lactate dehydrogenase release, reactive oxygen species generation, and mitochondrial membrane potential. The transcriptomic changes were measured using RNA sequencing, and bioinformatics characteristics including biological functions, signal pathways and protein-protein interaction were analyzed to explore the potential molecular mechanisms. Results displayed that the order of cytotoxicity was OH-TPHP> TPHP> DPHP. The prioritized biological functions changes induced by TPHP and OH-TPHP were correlated with lipid metabolism. Significant lipid accumulation was observed as confirmed by increased total cholesterol and triglycerides contents, and enhanced oil red O staining. Enrichment of PPARα/γ and down-stream genes suggested the participation of PPARs signal pathway in lipid metabolism disorder. In addition, TPHP and OH-TPHP induced endoplasmic reticulum stress (ERS), which was further confirmed by the ERS inhibitor experiment. In general, TPHP and OH-TPHP had obvious cytotoxic effects in HepG2 cells. PPARs signal pathway and endoplasmic reticulum stress may be involved in the lipid metabolism disorder induced by TPHP and OH-TPHP.

1688-P: Glucokinase Activator Triggers PERK-UPR Pathway in Diet-Induced Obese Mice via Inducing Hepatic Lipid Accumulation

Background: To investigate the effect of glucokinase activation on glucose and lipid metabolism in diet-induced obese mice. Methods: Mice fed with High-fat-diet (HFD) or control diet for 16 weeks were subjected to glucokinase activator (GKA) or vehicle treatment by gavage for 4 weeks. Glucose tolerance tests were performed to evaluate the glucose-lowering effect of GKA. Hepatic lipid accumulation was assessed by H&E, Oil-red’O staining, and transmission electronic microscopy. The underlying mechanism and subsequent effects of glucokinase activation-induced lipid accumulation was analyzed in liver. Protein levels of related genes were analyzed in mouse livers or AML12 cells. Results: Glucokinase activation improved glucose tolerance and insulin sensitivity in obese mice. Moreover, increased liver weight and TG Content were found in GKA-treated obese mice. Significant hepatic lipid accumulation was observed by multiple assays. RNA sequencing analysis indicated the increased expression of lipogenesis genes and activated PERK-UPR pathway in the liver. Inhibition of the lipogenesis-related gene Acc reduced the lipid levels caused by GKA treatment and alleviated PERK-UPR pathway in AML12 cell line. Conclusions: Glucokinase activation improved glucose tolerance while induced hepatic lipid accumulation through increased lipogenesis, which subsequently triggered PERK-UPR signaling pathway. Disclosure N.Cai: None. L.Zeng: None. X.Chen: None. J.Liu: None. Z.Wen: None. S.Wen: None. W.Zeng: None. S.Lin: None. Y.Chen: None. G.Shi: None. Funding National Natural Science Foundation of China (81770826, 82070811); National Key R&D Program of China (2017YFA0105803); Key Area R&D Program of Guangdong Province (2019B020227003); Sci-Tech Research Development Program of Guangzhou City (202201020497); Natural Science Foundation of Guangdong Province (2018B030311012)

1686-P: ER Stress Aggravates Diaphragmatic Weakness through Activating PERK/JNK Signaling in Obesity Hypoventilation Syndrome

Obesity hypoventilation syndrome (OHS) is associated with reduced quality of life and increased risk of death. Diaphragmatic dysfunction has been implicated in the pathogenesis of OHS. We found that significant diaphragmatic weakness and lipid accumulation in people with obesity as well as mouse models of obesity, which was associated with activated endoplasmic reticulum (ER) stress indicated by increased PERK signaling and activation of JNK pathway. In cultured myotubes, inhibition of PERK and JNK signaling abrogated the lipids deposition and ameliorated insulin resistance, and inhibition of JNK signaling reversed the impaired elasticity of myotubes induced by lipotoxicity. Collectively, our data suggest that activation of PERK/JNK signaling is an important pathophysiological factor contributing to diaphragmatic contractile dysfunction in OHS. Disclosure X.Xiang: None. Y.Zhu: None. X.Pan: None. W.Xin: None. W.Tang: None. X.He: None. G.Shi: None. Y.Chen: None. Funding National Key R&D Program of China (2017YFA0105803); National Natural Science Foundation of China (82270886, 82070811); 5010 Clinical Research Projects of Sun Yat-sen University (2015015); Science and Technology Plan Project of Guangzhou City (202007040003, 202201020497); Key Area R&D Program of Guangdong Province (2019B020227003); Science and Technology Research Development Program of Guangzhou City (202007040003, 202201020497)

Mettl3-mediated m6A modification plays a role in lipid metabolism disorders and progressive liver damage in mice by regulating lipid metabolism-related gene expression.

N6-methyladenosine (m6A), the most abundant and conserved epigenetic modification of mRNA, participates in various physiological and pathological processes. However, the roles of m6A modification in liver lipid metabolism have yet to be understood entirely. We aimed to investigate the roles of the m6A "writer" protein methyltransferase-like 3 (Mettl3) in liver lipid metabolism and the underlying mechanisms. We assessed the expression of Mettl3 in liver tissues of diabetes (db/db) mice, obese (ob/ob) mice, high saturated fat-, cholesterol-, and fructose-induced non-alcoholic fatty liver disease (NAFLD) mice, and alcohol abuse and alcoholism (NIAAA) mice by quantitative reverse-transcriptase PCR (qRT-PCR). Hepatocyte-specific Mettl3 knockout mice were used to evaluate the effects of Mettl3 deficiency in mouse liver. The molecular mechanisms underlying the roles of Mettl3 deletion in liver lipid metabolism were explored by multi-omics joint analysis of public data from the Gene Expression Omnibus database and further validated by qRT-PCR and Western blot. Significantly decreased Mettl3 expression was associated with NAFLD progression. Hepatocyte-specific knockout of Mettl3 resulted in significant lipid accumulation in the liver, increased serum total cholesterol levels, and progressive liver damage in mice. Mechanistically, loss of Mettl3 significantly downregulated the expression levels of multiple m6A-modified mRNAs related to lipid metabolism, including Adh7, Cpt1a, and Cyp7a1, further promoting lipid metabolism disorders and liver injury in mice. In summary, our findings demonstrate that the expression alteration of genes related to lipid metabolism by Mettl3-mediated m6A modification contributes to the development of NAFLD.

Label-Free Evaluation of Maturation and Hepatotoxicity of Human iPSC-Derived Hepatocytes Using Hyperspectral Raman Imaging.

To promote the clinical application of human induced pluripotent stem cell (hiPSC)-derived hepatocytes, a method capable of monitoring regenerative processes and assessing differentiation efficiency without harming or modifying these cells is important. Raman microscopy provides a powerful tool for this as it enables label-free identification of intracellular biomolecules in live samples. Here, we used label-free Raman microscopy to assess hiPSC differentiation into hepatocyte lineage based on the intracellular chemical content. We contrasted these data with similar phenotypes from the HepaRG and from commercially available hiPSC-derived hepatocytes (iCell hepatocytes). We detected hepatic cytochromes, lipids, and glycogen in hiPSC-derived hepatocyte-like cells (HLCs) but not biliary-like cells (BLCs), indicating intrinsic differences in biomolecular content between these phenotypes. The data show significant glycogen and lipid accumulation as early as the definitive endoderm transition. Additionally, we explored the use of Raman imaging as a hepatotoxicity assay for the HepaRG and iCell hepatocytes, with data displaying a dose-dependent reduction of glycogen accumulation in response to acetaminophen. These findings show that the nondestructive and high-content nature of Raman imaging provides a promising tool for both quality control of hiPSC-derived hepatocytes and hepatotoxicity screening.

Lipidomic insights into the response of Arabidopsis sepals to mild heat stress

Arabidopsis sepals coordinate flower opening in the morning as ambient temperature rises; however, the underlying molecular mechanisms are poorly understood. Mutation of one heat shock protein encoding gene, HSP70-16, impaired sepal heat stress responses (HSR), disrupting lipid metabolism, especially sepal cuticular lipids, leading to abnormal flower opening. To further explore, to what extent, lipids play roles in this process, in this study, we compared lipidomic changes in sepals of hsp70-16 and vdac3 (mutant of a voltage-dependent anion channel, VDAC3, an HSP70-16 interactor) grown under both normal (22 °C) and mild heat stress (27 °C, mild HS) temperatures. Under normal temperature, neither hsp70-16 nor vdac3 sepals showed significant changes in total lipids; however, vdac3 but not hsp70-16 sepals exhibited significant reductions in the ratios of all detected 11 lipid classes, except the monogalactosyldiacylglycerols (MGDGs). Under mild HS temperature, hsp70-16 but not vdac3 sepals showed dramatic reduction in total lipids. In addition, vdac3 sepals exhibited a significant accumulation of plastidic lipids, especially sulfoquinovosyldiacylglycerols (SQDGs) and phosphatidylglycerols (PGs), whereas hsp70-16 sepals had a significant accumulation of triacylglycerols (TAGs) and simultaneous dramatic reductions in SQDGs and phospholipids (PLs), such as phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and phosphatidylserines (PSs). These findings revealed that the impact of mild HS on sepal lipidome is influenced by genetic factors, and further, that HSP70-16 and VDAC3 differently affect sepal lipidomic responses to mild HS. Our studies provide a lipidomic insight into functions of HSP and VDAC proteins in the plant’s HSR, in the context of floral development.

Glyphosate-induced autophagy inhibition results in hepatic steatosis via mediating epigenetic reprogramming of PPARα in roosters

Glyphosate (Gly) is the most widely used herbicide with well-defined hepatotoxic effects, but the underlying mechanisms of Gly-induced hepatic steatosis remain largely unknown. In this study, a rooster model combined with primary chicken embryo hepatocytes was established to dissect the progresses and mechanisms of Gly-induced hepatic steatosis. Data showed that Gly exposure caused liver injury with disrupted lipid metabolism in roosters, manifested by significant serum lipid profile disorder and hepatic lipid accumulation. Transcriptomic analysis revealed that PPARα and autophagy-related pathways played important roles in Gly-induced hepatic lipid metabolism disorders. Further experimental results suggested that autophagy inhibition was involved in Gly-induced hepatic lipid accumulation, which was confirmed by the effect of classic autophagy inducer rapamycin (Rapa). Moreover, data substantiated that Gly-mediated autophagy inhibition caused nuclear increase of HDAC3, which altered epigenetic modification of PPARα, leading to fatty acid oxidation (FAO) inhibition and subsequently lipid accumulation in the hepatocytes. In summary, this study provides novel evidence that Gly-induced autophagy inhibition evokes the inactivation of PPARα-mediated FAO and concomitant hepatic steatosis in roosters by mediating epigenetic reprogramming of PPARα.

Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact.

Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.

Delayed First Feeding Chronically Impairs Larval Fish Growth Performance, Hepatic Lipid Metabolism, and Visceral Lipid Deposition at the Mouth-Opening Stage.

During the mouth-opening stage, fish larvae are susceptible to delayed first feeding (DFF). In this study, we explored the effects of DFF for two days on later growth and energy metabolism in larval fish. Results showed that DFF chronically impaired larval growth performance, thereby reducing the efficiency of feed utilization by larvae. In DFF larvae, the mRNA levels of growth inhibitors (i.e., igfbp1a and igfbp1b) were significantly upregulated and consistently maintained at high expression levels, which may be an important attribution of larval growth retardation. Concomitantly, DFF retarded the growth of adipose tissue and reduced lipid deposition in larval viscera, suggesting lipid metabolism is disordered in DFF larvae and generates inefficient lipid reserves. In the liver, we observed that DFF resulted in a significant accumulation of neutral lipids, and this phenotype did not disappear rapidly after DFF larvae received exogenous nutrition. As to the transcript analyses, we found that the expression of genes related to hepatic lipid synthesis (e.g., srebf1, srebf2, dgat1a, dgat1b, fasn, and scdb) in DFF larvae was consistently upregulated, while the expression of genes involved in lipid transport (e.g., apoa2, apoa4b.1, and apoa4b.3) was downregulated. Therefore, it appears that the inefficient lipid reserves in DFF larvae are associated with their hepatic lipid transport dysfunction. Taken together, our findings contribute to understanding the impairments to fish larvae caused by delayed first feeding during the mouth-opening stage and to aiding larval management in the aquaculture industry.