Hepatic Fatty Acid Metabolism Research Articles

Hovenia dulcis Fruit Peduncle Polysaccharides Reduce Intestinal Dysbiosis and Hepatic Fatty Acid Metabolism Disorders in Alcohol-Exposed Mice.

Alcohol abuse can lead to alcoholic liver disease, becoming a major global burden. Hovenia dulcis fruit peduncle polysaccharides (HDPs) have the potential to alleviate alcoholic liver injury and play essential roles in treating alcohol-exposed liver disease; however, the hepatoprotective effects and mechanisms remain elusive. In this study, we investigated the hepatoprotective effects of HDPs and their potential mechanisms in alcohol-exposed mice through liver metabolomics and gut microbiome. The results found that HDPs reduced medium-dose alcohol-caused dyslipidemia (significantly elevated T-CHO, TG, LDL-C), elevated liver glycogen levels, and inhibited intestinal-hepatic inflammation (significantly decreased IL-4, IFN-γ and TNF-α), consequently reversing hepatic pathological changes. When applying gut microbiome analysis, HDPs showed significant decreases in Proteobacteria, significant increases in Firmicutes at the phylum level, increased Lactobacillus abundance, and decreased Enterobacteria abundance, maintaining the composition of gut microbiota. Further hepatic metabolomics analysis revealed that HDPs had a regulatory effect on hepatic fatty acid metabolism, by increasing the major metabolic pathways including arachidonic acid and glycerophospholipid metabolism, and identified two important metabolites-C00157 (phosphatidylcholine, a glycerophospholipid plays a central role in energy production) and C04230 (1-Acyl-sn-glycero-3-phosphocholine, a lysophospholipid involved in the breakdown of phospholipids)-involved in the above metabolism. Overall, HDPs reduced intestinal dysbiosis and hepatic fatty acid metabolism disorders in alcohol-exposed mice, suggesting that HDPs have a beneficial effect on alleviating alcohol-induced hepatic metabolic disorders.

Dietary Resveratrol Ameliorates Hepatic Fatty Acid Metabolism and Jejunal Barrier in Offspring Induced by Maternal Oxidized Soybean Oil Challenge.

Increasing evidence indicates that maternal exposure to oxidized soybean oil (OSO) causes damage to the mother and offspring. The antioxidant resveratrol (Res) has a variety of health benefits. However, the protective effect of Res on mitigating offspring damage after maternal exposure to OSO and its mechanism remains unclear. Therefore, this study aimed to investigate the effect of Res on hepatic fatty acid metabolism and the jejunal barrier in suckling piglets after maternal OSO exposure. A total of 18 sows in late gestation were randomly assigned to three treatments. The sows were fed with a fresh soybean oil (FSO) diet, an OSO diet, or the OSO diet supplemented with 300 mg/kg Res (OSO + Res), respectively. The results showed that maternal supplementation of Res restored the mRNA levels of genes related to fatty acid metabolism and increased the activities of catalase (CAT) and total superoxide dismutase (T-SOD) in suckling piglets' livers under the OSO challenge. Moreover, the OSO + Res group restored the mRNA levels of occludin and claudin 4 in suckling piglet jejunum compared with the results of the OSO challenges. In summary, supplementation with Res improves hepatic fatty acid metabolism and intestinal barrier function of suckling piglets after maternal OSO challenge during late gestation and lactation.

Effect of dietary fats and soybean phospholipid on hepatic fatty acid metabolism in mice

Effect of dietary fats and soybean phospholipid on hepatic fatty acid metabolism in mice

Hepatic GRK2 is dispensable for glucose homeostasis and other key metabolic parameters in mice

ObjectiveG-protein-coupled receptor (GPCR) kinases (GRKs) abrogate GPCR signaling by promoting receptor desensitization and internalization. Accumulating evidence suggests that GRK2 represents an important regulator of GPCR-mediated effects on systemic glucose metabolism, obesity, and insulin resistance. Despite the key role of the liver in maintaining euglycemia, the potential metabolic relevance of hepatic GRK2 has yet to be examined. Thus, the goal of this study was to explore the potential role of hepatic GRK2 in maintaining glucose homeostasis and other key metabolic functions. MethodsTo address this question, we generated mice that showed a ∼90% reduction in GRK2 protein expression selectively in hepatocytes (Hep-GRK2-KO mice) and subjected these mice, together with their control littermates, to systematic metabolic phenotyping studies. ResultsWe found that Hep-GRK2-KO mice maintained on regular chow did not differ significantly from their control littermates in glycemia, glucose tolerance, insulin sensitivity, in vivo gluconeogenesis, and glucagon-induced hyperglycemia. We obtained similar findings when we analyzed Hep-GRK2-KO mice and control littermates consuming an obesogenic high-fat diet. Likewise, plasma levels of insulin, glucagon, free fatty acids, and ketone bodies remained unaffected by the lack of hepatocyte GRK2. The same was true when we examined the expression levels of key genes regulating hepatic glucose and fatty acid metabolism. ConclusionIn summary, our data suggest that hepatocyte GRK2 is dispensable for systemic glucose homeostasis and other key metabolic functions in both lean and obese mice. This finding suggests that drug development efforts aimed at inhibiting GRK2 to improve impaired glucose homeostasis and insulin sensitivity need to focus on other metabolically important tissues.

Broodstock nutritional programming differentially affects the hepatic transcriptome and genome-wide DNA methylome of farmed gilthead sea bream (Sparus aurata) depending on genetic background

BackgroundBroodstock nutritional programming improves the offspring utilization of plant-based diets in gilthead sea bream through changes in hepatic metabolism. Attention was initially focused on fatty acid desaturases, but it can involve a wide range of processes that remain largely unexplored. How all this can be driven by a different genetic background is hardly underlined, and the present study aimed to assess how broodstock nutrition affects differentially the transcriptome and genome-wide DNA methylome of reference and genetically selected fish within the PROGENSA® selection program.ResultsAfter the stimulus phase with a low fish oil diet, two offspring subsets of each genetic background received a control or a FUTURE-based diet. This highlighted a different hepatic transcriptome (RNA-seq) and genome-wide DNA methylation (MBD-seq) pattern depending on the genetic background. The number of differentially expressed transcripts following the challenge phase varied from 323 in reference fish to 2,009 in genetically selected fish. The number of discriminant transcripts, and associated enriched functions, were also markedly higher in selected fish. Moreover, correlation analysis depicted a hyper-methylated and down-regulated gene expression state in selected fish with the FUTURE diet, whereas the opposite pattern appeared in reference fish. After filtering for highly represented functions in selected fish, 115 epigenetic markers were retrieved in this group. Among them, lipid metabolism genes (23) were the most reactive following ordering by fold-change in expression, rendering a final list of 10 top markers with a key role on hepatic lipogenesis and fatty acid metabolism (cd36, pitpna, cidea, fasn, g6pd, lipt1, scd1a, acsbg2, acsl14, acsbg2).ConclusionsGene expression profiles and methylation signatures were dependent on genetic background in our experimental model. Such assumption affected the magnitude, but also the type and direction of change. Thus, the resulting epigenetic clock of reference fish might depict an older phenotype with a lower methylation for the epigenetically responsive genes with a negative methylation-expression pattern. Therefore, epigenetic markers will be specific of each genetic lineage, serving the broodstock programming in our selected fish to prevent and mitigate later in life the risk of hepatic steatosis through changes in hepatic lipogenesis and fatty acid metabolism.

Gene expression of hepatic gluconeogenic and fatty acid metabolism in early-lactation dairy cows as affected by dietary starch and monensin supplementation

Our previously published companion papers demonstrated improved production performance and energetic metabolism in cows fed diets with increased propiogenic potential in early lactation. Study objectives were to further explore effects of dietary starch content and monensin on hepatic gene expression of key enzymes related to gluconeogenesis and fatty acid metabolism in early lactation. From d 1 to 21 postpartum, primiparous (n = 16) and multiparous (n = 33) Holstein cows were fed a high (HS; 26.2% starch, 34.3% neutral detergent fiber, 22.7% acid detergent fiber, 15.5% crude protein) or low (LS; 21.5% starch, 36.9% neutral detergent fiber, 25.2% acid detergent fiber, 15.4% crude protein) starch diet with a daily topdress containing either 0 (Con) or 450 mg/d monensin (Mon). Cows were randomly assigned to treatment. Liver biopsies were obtained from cows on d 7 postpartum for DNA and RNA quantification and mRNA expression analysis. In primiparous cows, Mon supplementation decreased CPT1A expression relative to controls, whereas in multiparous cows Mon increased its expression. Cows fed HS and Mon tended to have decreased HMGCS2 expression relative to cows fed HS and Con. In multiparous cows, Mon supplementation tended to increase PC and PCK1 expression relative to controls. Correlation analysis was performed for all gene expression variables. Overall, relationships were similar in directionality and magnitude between cows fed HS and LS and Con and Mon. However, for cows fed Con there was a positive relationship between HMGCS2 and PC and HMGCS2 and PCK1, whereas for cows fed Mon there was no relationship. There was a similar lack of relationship between HMGCS2 and PC for cows fed HS. Overall, results support changes in performance and energetic metabolism reported in our companion papers, indicating that cows fed diets of different starch content in early lactation with Mon supplementation throughout the transition period had alterations in hepatic gene expression consistent with increased hepatic propionate supply.

Oxidized Soybean Oil Evoked Hepatic Fatty Acid Metabolism Disturbance in Rats and their Offspring.

The oxidation of fats and oils is an undisputed subject of science, given the effect of oxidized fats and oils on food quality and safety. This study aimed to determine whether maternal exposure to oxidized soybean oil (OSO) causes lipid metabolism disorders in the liver and whether this lipid metabolism disorder can be transmitted to offspring or even worsened. A total of 60 female Sprague-Dawley (SD) rats were divided randomly into four groups in this study. Treatment groups received a pure diet of OSO with a peroxide value of 200, 400, or 800 mEqO2/kg, while the control group received fresh soybean oil (FSO). As for our results, OSO affected serum biochemical parameters in the maternal generation (F0) and induced liver histopathology changes, inflammation, and oxidative stress. Moreover, the expression of genes related to the liver X receptor α (LXRα)─sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway was changed. Similar trends were found in the livers of offspring on postnatal days 21 and 56. In conclusion, exposure to OSO during gestation and lactation can affect liver lipid synthesis. Additionally, it is detrimental to the development of the offspring's liver, affecting fatty acid metabolism and causing liver damage.

Effect of Parenteral Supplementation of Minerals and Vitamins on Oxidative Stress Biomarkers and Hepatic Fatty Acid Metabolism in Dairy Cows During the Transition Period.

In the present work we aimed to study the effects of parenteral vitamin and mineral supplementation on hepatic fatty acid metabolism as well as on the oxidative stress biomarkers in biological samples of transition cows. The supplemented group (SG, n = 11) received a subcutaneous injection of 5mL of vitamin A palmitate 35mg/mL, vitamin E acetate 50mg/mL plus other injection of 5mL of copper edetate 10mg/mL, zinc edetate 40mg/mL, manganese edetate 10mg/mL, and sodium selenite 5mg/mL on days - 60, - 30, and 7 (± 3) relative to calving. The control group (CG, n = 11) received two subcutaneous injections of 5mL of 9mg/mL sodium chloride at the same times of the SG. Blood, urine, and liver biopsies were sampled 21 (± 3) days before the expected calving date and 7 and 21 (± 3) days after calving. Results revealed that supplemented animals had higher glutation peroxidase (GSH-Px) activity, lower and higher concentration of 3-nitrotyrosine (3-NT) in the liver and plasma, respectively, higher expression of the mitochondrial beta-oxidation enzyme carnitine palmitoyltransferase 1 in the liver, and lower content of hepatic triacylglycerol, mirroring plasma liver function parameters. No differences between groups were found in the superoxide dismutase activity, MDA concentrations, the protein abundance of peroxisomal acyl-CoA oxidase 1, diacylglycerol O-acyltransferase 1, and peroxisome proliferator-activated receptor alpha. These results suggest that the vitamin and mineral supplementation provided to dairy cows had a beneficial effect on GSH-Px activity, hepatic 3-NT concentration, and on the metabolic adaptation during the peripartum period.

Exercise Equals the Mobilization of Visceral versus Subcutaneous Adipose Fatty Acid Molecules in Fasted Rats Associated with the Modulation of the AMPK/ATGL/HSL Axis.

Combining exercise with fasting is known to boost fat mass-loss, but detailed analysis on the consequential mobilization of visceral and subcutaneous WAT-derived fatty acids has not been performed. In this study, a subset of fasted male rats (66 h) was submitted to daily bouts of mild exercise. Subsequently, by using gas chromatography-flame ionization detection, the content of 22 fatty acids (FA) in visceral (v) versus subcutaneous (sc) white adipose tissue (WAT) depots was compared to those found in response to the separate events. Findings were related to those obtained in serum and liver samples, the latter taking up FA to increase gluconeogenesis and ketogenesis. Each separate intervention reduced scWAT FA content, associated with increased levels of adipose triglyceride lipase (ATGL) protein despite unaltered AMP-activated protein kinase (AMPK) Thr172 phosphorylation, known to induce ATGL expression. The mobility of FAs from vWAT during fasting was absent with the exception of the MUFA 16:1 n-7 and only induced by combining fasting with exercise which was accompanied with reduced hormone sensitive lipase (HSL) Ser563 and increased Ser565 phosphorylation, whereas ATGL protein levels were elevated during fasting in association with the persistently increased phosphorylation of AMPK at Thr172 both during fasting and in response to the combined intervention. As expected, liver FA content increased during fasting, and was not further affected by exercise, despite additional FA release from vWAT in this condition, underlining increased hepatic FA metabolism. Both fasting and its combination with exercise showed preferential hepatic metabolism of the prominent saturated FAs C:16 and C:18 compared to the unsaturated FAs 18:1 n-9 and 18:2 n-6:1. In conclusion, depot-specific differences in WAT fatty acid molecule release during fasting, irrelevant to their degree of saturation or chain length, are mitigated when combined with exercise, to provide fuel to surrounding organs such as the liver which is correlated with increased ATGL/ HSL ratios, involving AMPK only in vWAT.

Differential effects of bariatric surgery and caloric restriction on hepatic one-carbon and fatty acid metabolism

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to ad-libitum (AL)-fed controls. Analysis of liver and blood metabolome and transcriptome revealed distinct and sometimes contrasting metabolic effects between the two interventions. SG primarily influenced one-carbon metabolic pathways, whereas IF-CR increased de novo lipogenesis and glycogen storage. These findings suggest that the unique metabolic pathways affected by SG and IF-CR contribute to their distinct clinical benefits, with bariatric surgery potentially influencing long-lasting changes through its effect on one-carbon metabolism.

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet mitochondria (PDM) and cytosolic mitochondria (CM) reveals that CM are enriched in proteins comprising various oxidative metabolism pathways, whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirms that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete medium. Additionally, mitochondrion-associated membranes (MAM) around PDM and CM differ in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways, whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity.

Metabolic role of the hepatic valine/3-hydroxyisobutyrate (3-HIB) pathway in fatty liver disease

The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation. HIBCH mRNA in human liver biopsies ("Liver cohort") and plasma 3-HIB ("CARBFUNC" cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays. We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS. These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention. Funding was provided by the Research Council of Norway (263124/F20), the University of Bergen, the Western Norway Health Authorities, Novo Nordisk Scandinavia AS, the Trond Mohn Foundation and the Norwegian Diabetes Association.

Carnitine Palmitoyltransferase Modulation of Hepatic Fatty Acid Metabolism and Radio-HPLC Evidence for Low Ketogenesis in Neonatal Pigs

A neonatal piglet model was used to study hepatic fatty acid metabolism during the early postnatal period. Hepatocytes were isolated from pigs at birth or after 24 h, in fed or unfed states (n = 4 pigs/group). Cells were incubated with 1 mmol/L [1-14C]-octanoate (C8) or -palmitate (C16) in the presence or absence of 1 mmol/L L-carnitine, carnitine plus tetra-decylglycidic acid (TDGA; 10 µmol/L) or carnitine plus glucagon (0.5 µg/L). Accumulation of radiolabel [nmol/(h · 106 cells)] in CO2 and acid-soluble products (ASP) was higher (3.5- and 4.5-fold, respectively) from C8 than from C16 (P < 0.0001). Glucagon, carnitine and TDGA had no effect on the oxidation of C8 (P > 0.1). Carnitine addition tended to increase C16 flux to ASP [from 5.3 to 7.6 nmol/(h · 106 cells); P < 0.1], whereas carnitine plus TDGA decreased flux (from 7.6 to 2.1; P < 0.001). Esterified products accounted for 70% of metabolized label in control C16 incubations; this was reduced to 62% by carnitine (P < 0.05) and increased to 80% by the addition of carnitine plus TDGA (P < 0.0001). The 1-14C flux to CO2 in cells from 24-h-old unfed piglets was 47% lower than from fed pigs (P < 0.01) but 28% higher than in pigs at birth. Radiolabel contained in ASP and total metabolized label were 48% lower from unfed pigs compared with the piglets at birth and 24-h-old fed pigs (P < 0.01) and were paralleled by changes in oxygen consumption. Radio-HPLC analysis of ASP revealed minimal radiolabel accumulation in ketone bodies. Up to 40% of radioactivity in ASP was presumptively identified as acetate. These data illustrate that hepatic C16 metabolism in piglets can be altered by changes in the activity of carnitine palmitoyltransferase I during the neonatal period and that ketone bodies do not represent a major route of hepatic fatty acid carbon flux.

Developmental changes in lipid and fatty acid metabolism and the inhibition by in ovo feeding oleic acid in Muscovy duck embryogenesis.

Hepatic lipid and fatty acid (FA) metabolism are critical for regulating energetic homeostasis during embryogenesis. At present, it remains unclear how an exogenous FA intervention affects embryonic development in an avian embryo model. In Exp. 1, 30 fertilized eggs were sampled on embryonic days (E) 16, 19, 22, 25, 28, 31 and the day of hatch (DOH) to determine the critical period of lipid metabolism. In Exp. 2, a total of 120 fertilized eggs were divided into two groups (60 eggs/group) for in ovo feeding (IOF) procedures on E25. Eggs were injected into the yolk sac with PBS as the control group and with oleic acid (OA) as the IOF-OA treatment group. Samples were collected on E28 and E31. In Exp. 1, hepatic triacylglycerol (TG) and cholesterol (CHO) contents increased while serum TG content decreased from E16 to DOH (P<0.05). Both serum and liver displayed an increase in unsaturated FA and a decrease in saturated FA (P<0.05). There was a quadratic increase in the target gene and protein expression related to hepatic FA de novo synthesis and oxidation (P<0.05), whose inflection period was between E22 and E28. In Exp. 2, compared with the control embryos, IOF-OA embryos had an increased yolk sac TG content on E28 and E31, and a decreased serum TG and CHO content on E28 (P<0.05). The IOF-OA embryos had less OA in the yolk sac and liver on E28, and less unsaturated FA in the serum and liver on E31 than did the control embryos (P<0.05). Hepatic gene mRNA expression related to FA uptake, synthesis, and oxidation on E28 was lower in IOF-OA than in control embryos (P<0.05), not on E31 (P>0.05). Maximal metabolic changes in lipid and FA metabolism occurred on E22-E28 in Muscovy duck embryogenesis, along with the altered target gene and protein expression related to lipogenesis and lipolysis. IOF-OA intervention on E25 could inhibit the target gene expression related to FA uptake, synthesis, and oxidation, which may influence the normal FA metabolism on E28 during embryogenesis.

Airborne PM2.5 pollution: A double-edged sword modulating hepatic lipid metabolism in middle-aged male mice

Emerging evidence suggests that exposure to airborne fine particulate matter (PM2.5) is closely related to disturbances in hepatic lipid metabolism. However, no systematic study assessed the age vulnerability in effects of PM2.5 exposure on metabolism, and the potential mechanisms remain unknown. This study aimed to investigate the metabolic susceptibility of different life stages to PM2.5 exposure, and to evaluate the underlying molecular mechanisms. Male C57BL/6 mice at three life phases (young, adult, and middle-aged) were exposed simultaneously to concentrated ambient PM2.5 or filtered air (FA) for 8 weeks using a whole-body inhalational exposure system. The average daily PM2.5 concentrations to which mice were actually exposed were 90.71 ± 7.99 μg/m3. The body weight, total food utilization, body composition, glucose metabolic homeostasis of the mice were evaluated. At euthanasia, serum and liver samples were collected to measure lipid profiles and hepatic function. H&E and Oil Red O staining were used to assess the liver cellular structure and hepatic lipid deposition. Transcriptomics and lipidomics were performed to determine the differentially expressed genes and lipid metabolites in the liver. Quantitative RT-PCR and immunoblots were performed to verify the transcriptomics and explore the mechanism for metabolic susceptibility. PM2.5 exposure led to reductions in body weight gain, total food utilization, and fat mass in middle-aged mice but not in young or adults. Exposure to PM2.5 reduced hepatic lipid deposition by enhancing lipolysis and inhibiting the glycerol-3-phosphate (G3P) pathway of hepatic lipogenesis. Furthermore, PM2.5 exposure attenuated hepatic fatty acid metabolism and primary bile acid biosynthesis. Finally, PM2.5 exposure dysregulated hepatic phospholipid metabolism, as evidenced by increased glycerophospholipid synthesis and disturbed sphingolipid metabolism. Therefore, middle-aged male mice were more vulnerable to PM2.5 exposure with double-edged effects, improved metabolism and hepatic TG accumulation but inhibited hepatic fatty acid and bile acid metabolism and dysregulated phospholipid metabolism.

Effect of dietary concentrations of metabolizable energy and neutral detergent fiber on productive performance, egg quality, fatty liver incidence, and hepatic fatty acid metabolism in aged laying hens

The objective of the current experiment was to investigate the effect of dietary concentrations of ME and neutral detergent fiber (NDF) on productive performance, egg quality, fatty liver incidence, and hepatic fatty acid metabolism in aged laying hens. A total of three hundred twenty 75-wk-old Hy-Line Brown laying hens were allotted to 1 of 4 dietary treatments with 8 replicates. Each replicate consisted of 10 consecutive cages with 1 hen per cage. The experiment was conducted using a completely randomized design with 2×2 factorial arrangement consisting of 2 levels of ME (normal [commercially recommended AMEn levels; 2,730 kcal/kg] and low [50 kcal/kg reduction in AMEn; 2,680 kcal/kg]) and 2 levels of NDF (low [9.01 and 9.61%; normal-ME and low-ME diets, respectively] and high [12.57 and 13.42%; normal-ME and low-ME diets, respectively]) in the diet. The diets and water were provided to hens on an ad libitum basis for 12 wk. Results indicated that no interactions between dietary concentrations of ME and NDF were observed for all measurements except for egg yolk color, eggshell thickness, and 2 hepatic gene expressions (i.e., carnitine palmitoyl transferase 1A and malic enzyme). For the main effects, increasing NDF concentrations in diets increased (P < 0.05) feed intake without affecting other productive performance. Hens fed normal-ME and high-NDF diets showed the darkest (P < 0.05) egg yolk color among those fed treatment diets, showing an interaction (P < 0.05). Increasing NDF concentrations in low-ME diets did not influence eggshell thickness, but those in normal-ME diets increased eggshell thickness in laying hens, showing an interaction (P < 0.05). For the main effects, increasing concentrations of dietary NDF or ME reduced (P < 0.05) hepatic fat concentrations with decreasing expressions in several genes related to fatty acid synthesis. In conclusion, increasing NDF concentrations in commercially-recommended ME diets decrease hepatic fat concentrations in aged laying hens, and therefore, may have a preventative effect on the fatty liver development in aged laying hens.

Gypenosides Improve Lipid Homeostasis by Regulating Fatty Acid Metabolism in the Liver

We have examined the effect of gypenosides on hepatic lipid metabolism in hyperlipidemic mice. To this end, male mice were placed on a high-fat diet and then administered gypenosides. Compared to the mice on the high-fat diet, the levels of liver index, total cholesterol, and low-density lipoprotein cholesterol in the serum were significantly reduced by gypenoside treatment. Gypenosides influenced the overall profile of 22 hepatic fatty acid metabolism genes significantly. Three genes, Cyp4a10, Cyp4a14, and Cyp4a31, had their mRNA expression altered by about tenfold. As a possible mechanism, the findings suggest that gypenosides regulate lipid homeostasis by influencing fatty acid metabolism and promoting fatty acid ω-oxidation.

PFOS-elicited metabolic perturbation in liver and fatty acid metabolites in testis of adult mice.

Multiple factors can contribute to sub-fecundity, including genetics, lifestyle, and environmental contaminants. PFASs are characterized as "forever chemicals" due to their ubiquitous contamination and their persistence in the environment, wildlife, and humans. Numerous studies have demonstrated that PFAS exposure adversely affects multiple bodily functions, including liver metabolism and gonadal function. It is unclear, however, how the disruption of hepatic fatty acid metabolism affects testicular function. In this study, male mice were administered 0.3 and 3 μg/g body weight of PFOS for 21 days. Our data showed that PFOS exposure caused hepatic steatosis, as evidenced by significant increases in triglyceride levels, expression of ATP-citrate lyase, and fatty acid synthase, as well as fasting insulin levels. PFOS perturbed the expression levels of hepatokines, of which fibroblast growth factor-21 (Fgf-21), leukocyte cell-derived chemotaxin-2 (Lect-2), and retinol-binding protein-4 (Rbp-4) were significantly reduced, whereas angiopoietin-like 4 (Angptl4) was noticeably increased. While Rbp-4 and Fgf-21 are known to contribute to spermatogenesis and testosterone synthesis. In PFOS-exposed groups, testicular ATP, and testosterone decreased significantly with a significant increase in the expression of peroxisome proliferator-activated receptor-coactivator 1α. Mass spectrophotometry imaging revealed the localization of PFOS in testes, along with significant increases in fatty acid metabolites. These included arachidonic acid, dihomo-α-linolenic acid, dihomo-γ-linolenic acid, oxidized ceramide, diacylglycerol, phosphatidylcholine, and phosphatidylethanolamine, which are associated with inflammation and post-testicular causes of infertility. This study revealed potential links between PFOS-elicited changes in hepatic metabolism and their impacts on testicular biology. This study provides insights into alternative targets elicited by PFOS that can be used to develop diagnostic and therapeutic strategies for improving testicular dysfunction.

Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis

BackgroundAlcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). MethodsWe performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). ResultsWe found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. ConclusionsACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.

Effects of Coix Seed Oil on High Fat Diet-Induced Obesity and Dyslipidemia.

Dietary intervention is becoming more popular as a way to improve lipid metabolism and reduce the prevalence of diet-related chronic disorders. We evaluated the effects of several dietary oils on body weight, fat mass, liver weight, and tumor necrosis factor in obese mice given a high-fat diet (HFD) to discover if coix seed oil (CSO) had an anti-obesity impact. As compared to other dietary fats, CSO treatment considerably lowered body weight and liver index, successfully sup-pressed total cholesterol and triglyceride content, and raised liver lipid deposition and lipid metabolism problem induced by high fat intake. Furthermore, gas chromatography research revealed that CSO extracted by supercritical fluid, with 64% being CSO extracted by supercritical fluid, and the greatest amounts of capric acids and lauric acids being 35.28% and 22.21%, respectively. CSO contained a high content of medium-chain fatty acids and was able to modify hepatic fatty acid metabolism and lipid levels in HFD-induced obese mice. According to the results, CSO has the potential to replace dietary lipids as a promising functional lipid in the prevention of met-abolish disorders.