Liver Triglyceride Content Research Articles

Down-regulation of miR-29 improves lipid metabolism in fatty liver of dairy cows

In this study, we conducted a thorough investigation into the mechanisms by which miR-29 influences lipid metabolism. Thirty-two cows were selected and categorized into distinct groups based on their liver triglyceride (TG) content: healthy, mild fatty liver, and moderate fatty liver groups. Dairy cows with moderate fatty liver showed higher levels of hepatic lipid accumulation, MDA content and serum AST, ALT and ALP contents and lower hepatic catalase CAT and SOD activities. Subsequently, hepatocytes isolated from healthy calves were exposed to sodium oleate (SO) in the presence or absence of pre-incubation with miR-29 inhibitor or inhibitor NC. Pre-transfection with miR-29 inhibitor resulted in reduced hepatocyte lipid accumulation and MDA levels, as well as decreased levels of AST, ALT, and ALP in the supernatant. In the miR-29 inhibitor + SO group, there was an increase in the expression of SREBP-1, FAS, SCD1, and Sirt1. Meanwhile, the expression of PPARα, CPT1, CPT2, PGC-1α, NRF-1, UCP2, and miR-29 were observed to be decreased. In comparison to the miR-29 inhibitor + SO group, some of the measured indicators showed partial reversal in the miR-29 inhibitor + siSirt1 + SO group. Collectively, these findings provide evidence that miR-29 may play a crucial role in the pathogenesis of fatty liver in dairy cows.

Letter to the Editor From Fu et al: "Machine Learning Reveals the Contribution of Lipoproteins to Liver Triglyceride Content and Inflammation".

Letter to the Editor From Fu et al: "Machine Learning Reveals the Contribution of Lipoproteins to Liver Triglyceride Content and Inflammation".

Dietary manganese supplementation decreases hepatic lipid deposition by regulating gene expression and enzyme activity involved in lipid metabolism in the liver of broilers.

This study aimed to characterize the effects of different dietary forms of supplemental manganese (Mn) on hepatic lipid deposition, gene expression, and enzyme activity in liver fat metabolism in 42-d-old broiler chickens. In total 420 one-day-old Arbor Acres (AA) broilers (rooster:hen = 1:1) were assigned randomly based on body weight and sex to 1 of 6 treatments (10 replicate cages per treatment and 7 broilers per replicate cage) in a completely randomized design using a 2 (sex) × 3 (diet) factorial arrangement. The 3 diets were basal control diets without Mn supplementation and basal diets supplemented with either Mn sulfate or Mn proteinate. No sex × diet interactions were observed in any of the measured indexes; thus, the effect of diet alone was presented in this study. Dietary Mn supplementation increased Mn content in the plasma and liver, adipose triglyceride lipase (ATGL) activity, and ATGL mRNA and its protein expression in the liver by 5.3% to 24.0% (P < 0.05), but reduced plasma triglyceride (TG), total cholesterol, and low-density lipoprotein (LDL-C) levels, liver TG content, fatty acid synthase (FAS) and malic enzyme (ME) activities, mRNA expression of sterol-regulatory element-binding protein 1 (SREBP1), FAS, stearoyl-coA desaturase (SCD), and ME, as well as the protein expression of SREBP1 and SCD in the liver by 5.5% to 22.8% (P < 0.05). No differences were observed between the 2 Mn sources in all of the determined parameters. Therefore, it was concluded that dietary Mn supplementation, regardless of Mn source, decreased hepatic lipid accumulation in broilers by inhibiting SREBP1 and SCD expression, FAS and ME activities, and enhancing ATGL expression and activity.

Thermoneutrality Inhibits Thermogenic Markers and Exacerbates Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a "fast food" diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.

Dietary supplementation with 25-hydroxyvitamin D3 regulates productive performance, lipid metabolism and gut microbiota in aged laying ducks

The aim of this study was to investigate the effect of dietary supplementation with 25-hydroxyvitamin D3 (25(OH)D3) on productive performance, lipid metabolism and gut microbiota in aged laying ducks. A total of 432 healthy Longyan ducks at 60-week of age were randomly allotted to 6 groups, each with 6 replicates of 12 ducks. Ducks were given a basal diet (without added 25(OH)D3) or that diet supplemented with 800, 1600, 2400, 3200, or 4000 IU/kg 25(OH)D3 for a total of 16 wk. Dietary supplementation with 25(OH)D3 improved egg production, egg mass and average daily feed intake, and decreased the feed conversion ratio (FCR) of ducks during the whole trial period (linear, quadratic; P < 0.05). Supplementation with 25(OH)D3 decreased very low-density lipoprotein (VLDL) content in yolk (P = 0.008), decreased high-density lipoprotein and low-density lipoprotein (LDL) content in plasma (P = 0.002). Hepatic index, VLDL, LDL, triglyceride and total cholesterol content in liver, nonalcoholic fatty liver activity score of liver and alanine aminotransferase content in plasma were decreased with supplementation of 25(OH)D3 (linear or quadratic; P < 0.05). The decreased hepatic apolipoprotein B 100 and lipoprotein lipase expression, and increased hepatic peroxisome proliferator-activated receptor-α and sterol regulatory element binding protein-1 expression resulted from 25(OH)D3 supplementation (linear, quadratic; P < 0.05). Moreover, 25(OH)D3 supplementation increased the villus/crypt ratio (linear, quadratic; P < 0.05) and expression of zonula occludens protein 1 and nuclear factor-κ-gene binding in duodenum (P < 0.05). The supplementation of 25(OH)D3 reduced the abundance of Wittenberg polluted soil-2 bacteria, Synergistota, Bacteroidales, Colidextribacter, Eggerthellaceae, Oscillospira, Oscillibacter, UCG-009, Barnesiellaceae and Lachnospiraceae_UCG-010 in cecal contents (P < 0.05). Dietary requirements for 25(OH)D3 for ducks (60 to 76 wk), were estimated to be 3377 IU/kg for egg production, 3434 IU/kg for egg mass, and 3256 IU/kg for FCR. In summary, dietary 25(OH)D3 supplementation improved productive performance and influenced liver and plasma lipid homeostasis in aged laying ducks, which may be associated with the reduction of bacteria involved in carbohydrate metabolism in the cecum. Supplementing the basal diet with 3250 to 3450 IU/kg 25(OH)D3 is recommended for aged laying ducks (60 to 76 wk).

Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides.

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

Effects of abomasal infusion of branched-chain amino acids or branched-chain keto-acids on liver function, inflammation, and oxidative stress in multiparous fresh cows

Reduced liver function, increased oxidative stress, and inflammation in early lactation negatively impact lactation performance and health of fresh cows. Previous findings from our group demonstrated that branched-chain amino acids (BCAA) infusion improved lactation performance and branched-chain ketoacids (BCKA) infusion decreased liver triglyceride (TG) in fresh cows. The objectives of this study were to determine the effect of BCAA and BCKA on blood and liver biomarkers of liver function, oxidative stress, and inflammation as well as expression of genes regulating inflammation and antioxidant metabolism in the liver. Thirty multiparous Holstein cows were used in a randomized block design receiving continuous abomasal infusion for 21 d after parturition. Treatments (10 cows each) were control (CON), cows abomasally infused with 0.9% saline; BCA, cows abomasally infused with BCAA (67 g valine, 50 g leucine, and 34 g isoleucine); and BCK, cows abomasally infused with BCKA (77 g ketovaline, 57 g ketoleucine, and 39 g ketoisoleucine). All cows were randomly assigned to treatments after parturition and received the same diet throughout the experimental period. Blood was collected at 3, 7, 14, and 21 d postpartum for liver function, oxidative stress, and inflammation biomarker profiling. Liver was also harvested on 7, 14, and 21 d postpartum for quantification of glutathione, protein carbonylation, and expression of genes. ANOVA was conducted for all data using PROC GLIMMIX in SAS. No treatment differences were observed for liver function biomarkers (bilirubin, gamma-glutamyl transferase, and aspartate aminotransferase). Cows receiving BCAA had lower blood NO2- and NO3- concentrations compared with CON. A tendency for lower advanced oxidized protein products was also observed in BCA cows compared with CON. Additionally, on d 7, BCA cows had lower protein carbonylation in the liver compared with CON. In contrast, BCK cows had higher plasma thiol and albumin, as well as liver reduced and total glutathione compared with CON cows. Compared with CON, BCK cows had higher expression glutathione reductase in the liver. Overall, these results suggest favorable alterations in oxidative stress and inflammation status in fresh cows receiving BCAA or BCKA infusion during the first 3 weeks of lactation, which likely contributed to previously-observed changes in lactation performance and liver TG concentrations. Future work is required to evaluate the interrelated metabolism of BCAA and BCKA to better understand their effects on oxidative and immune metabolism.

Machine learning reveals the contribution of lipoproteins to liver triglyceride content and inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide and is strongly associated with metabolic comorbidities, including dyslipidemia. Herein, we aim to estimate the prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in Europeans with isolated hypercholesterolemia and isolated hypertriglyceridemia in the UK Biobank and to estimate the independent contribution of lipoproteins to liver triglyceride content. We selected 218,732 Europeans from the UK Biobank without chronic viral hepatitis and other causes of liver disease, of whom 14,937 with liver magnetic resonance imaging (MRI) data available. Next, to examine the relationships between traits in predicting liver triglyceride content, we compared the predictive performance of several machine learning methods and selected the best performing algorithms based on the minimum cross-validated mean squared error (MSE). There was an approximately 3-fold and 4-fold enrichment of MASLD and MASH in individuals with isolated hypertriglyceridemia (p=1.23E-41 and p=1.29E-10, respectively), whereas individuals with isolated hypercholesterolemia had a marginal higher rate of MASLD and no difference in MASH rate compared to control group (p=0.019 and p=0.97, respectively). Among machine learning methods, feed-forward neural network had the best cross-validation MSE on the validation set. Circulating triglycerides, after body mass index (BMI), were the second strongest independent predictor of liver proton density fat fraction (PDFF) with the largest absolute mean Shapley additive explanation (SHAP) value. Isolated hypertriglyceridemia is the second strongest, after obesity, independent predictor of MASLD/MASH. Individuals with hypertriglyceridemia, but not with hypercholesterolemia, should be screened for liver disease.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 μM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fractionin both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Dietary lipid sources affect growth performance, lipid deposition, antioxidant capacity and inflammatory response of largemouth bass (Micropterus salmoides)

The present study explored the effects of different lipid sources on growth performance, lipid deposition, antioxidant capacity, inflammatory response and disease resistance of largemouth bass (Micropterus salmoides). Four isonitrogenous (crude protein 50.46 %) and isolipidic (crude lipid 11.12 %) diets were formulated to contain 7 % of different oil sources including fish oil (FO) (control), soybean oil (SO), linseed oil (LO) and coconut oil (CO). Largemouth bass with initial body weight of 36.0 ± 0.2 g were randomly distributed into 12 tanks, with 30 fish per tank and 3 tanks per treatment. The fish were fed with the experiment diets twice daily for 8 weeks. The results indicated that the weight gain of largemouth bass fed the FO diet was significantly higher than that of fish fed the LO and CO diets. The liver crude lipid content in FO group was significantly higher than other groups, while the highest liver triglyceride content was showed in SO group and the lowest was detected in LO group. At transcriptional level, expression of lipogenesis related genes (pparγ, srebp1, fas, acc, dgat1 and dgat2) in the SO and CO group were significantly higher than the FO group. However, the expression of lipolysis and fatty acids oxidation related genes (pparα, cpt1, and aco) in vegetable oils groups were significantly higher than the FO group. As to the antioxidant capacity, vegetable oils significantly reduced the malondialdehyde content of largemouth bass. Total antioxidant capacity in the SO and LO groups were significantly increased compared with the FO group. Catalase in the LO group was significantly increased compared with the FO group. Furthermore, the ER stress related genes, such as grp78, atf6α, atf6β, chop and xbp1 were significantly enhanced in the vegetable oil groups compared with the FO group. The activity of serum lysozyme in vegetable oil groups were significantly higher than in FO group. Additionally, the relative expression of non-specific immune related genes, including tlr2, mapk11, mapk13, mapk14, rela, tgf-β1, tnfα, 5lox, il-1β and il10, were all significantly increased in SO and CO groups compared to the other groups. In conclusion, based on the indexes including growth performance, lipid deposition, antioxidant capacity and inflammatory response, SO and LO could be alternative oil sources for largemouth bass.

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

BackgroundGoose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant energy intake. As a result, goose offers an excellent model for studying obesity, metabolic disorders, and liver diseases in mammals. Although the impact of the three-dimensional arrangement of chromatin within the cell nucleus on gene expression and transcriptional regulation is widely acknowledged, the precise functions of chromatin architecture reorganization during fat deposition in goose liver tissues still need to be fully comprehended.ResultsIn this study, geese exhibited more pronounced changes in the liver index and triglyceride (TG) content following the consumption of the high-fat diet (HFD) than mice without significant signs of inflammation. Additionally, we performed comprehensive analyses on 10 goose liver tissues (5 HFD, 5 normal), including generating high-resolution maps of chromatin architecture, conducting whole-genome gene expression profiling, and identifying H3K27ac peaks in the livers of geese and mice subjected to the HFD. Our results unveiled a multiscale restructuring of chromatin architecture, encompassing Compartment A/B, topologically associated domains, and interactions between promoters and enhancers. The dynamism of the three-dimensional genome architecture, prompted by the HFD, assumed a pivotal role in the transcriptional regulation of crucial genes. Furthermore, we identified genes that regulate chromatin conformation changes, contributing to the metabolic adaptation process of lipid deposition and hepatic fat changes in geese in response to excessive energy intake. Moreover, we conducted a cross-species analysis comparing geese and mice exposed to the HFD, revealing unique characteristics specific to the goose liver compared to a mouse. These chromatin conformation changes help elucidate the observed characteristics of fat deposition and hepatic fat regulation in geese under conditions of excessive energy intake.ConclusionsWe examined the dynamic modifications in three-dimensional chromatin architecture and gene expression induced by an HFD in goose liver tissues. We conducted a cross-species analysis comparing that of mice. Our results contribute significant insights into the chromatin architecture of goose liver tissues, offering a novel perspective for investigating mammal liver diseases.

High Fat Diet Induced Lipid Deposition and Perilipin 2 Expression in Mouse Liver Is Attenuated by Endothelin-1 Receptor A Blockade

Obesity is associated with dyslipidemia and lipid deposition into liver tissue. Circulating endothelin-1 (ET-1) is elevated in patients with obesity, and our lab has demonstrated that ET-1 is increased in liver of mice fed high fat (HFD). Interestingly, treatment with atrasentan attenuates reduces circulating triglycerides and free fatty acids and reduces lipid deposition into liver of mice fed HFD for 10 weeks; however, the mechanisms are not known. Perilipin 2 (Plin2) is a protein expressed in adipocytes and hepatocytes that is integral to lipid droplet formation by forming a coating around the droplet. We hypothesized that ET-1 receptor blockade reduces liver lipid deposition in obese mice by reducing Plin2 expression. To test this hypothesis, mice were fed normal (NMD) or HFD for 10 weeks and treated with the ET-1 receptor A (ETA) antagonist atrasentan for weeks 9-10. ET-1 receptor expression was significantly increased in HFD fed mice compared to NMD. As previously demonstrated, HFD fed mice had significantly higher liver triglyceride content compared to NMD controls, and this was attenuated in mice treated with atrasentan (ATR). As expected, Plin2 expression in liver tissue was significantly elevated in HFD mice compared to NMD (91.7±17.4 vs. 60.8±14.4 copies/pg RNA), an affect that was abolished in mice treated with atrasentan (NMD, 60.8±14.4; HFD, 91.7±17.4; NMD + ATR, 70.2±10.8; HFD + ATR, 26.3±5.8 copies/10pg RNA). These data suggest that ET-1 promotes lipid accumulation in liver of obese mice by reducing Plin2 expression. Funding: R01 DK124437, P30GM149404, and T32HL105324. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Low serum manganese as a noninvasive marker predicting the presence of myosteatosis among hospitalized patients with cirrhosis

Emerging evidence expands on a close connection between trace elements and muscular abnormalities, mostly focusing on sarcopenia. We hypothesized an association between concentrations of serum trace elements and myosteatosis, given that myosteatosis has a more pronounced clinical implication relative to sarcopenia, but there is a paucity of data in patients with cirrhosis. Consecutive patients were hospitalized for cirrhosis-associated complications. Serum trace elements (zinc, copper, manganese [Mn], magnesium, calcium, and iron) were measured by inductively coupled plasma mass spectrometry. The presence of myosteatosis was defined according to computed tomography–demarcated intramuscular adipose tissue content. In total, the 295 patients with cirrhosis analyzed had a median age of 63 years and 53.6% were male. Among them, 42 patients presented with myosteatosis (14.2%) and concomitant higher Model for End-stage Liver Disease-Sodium and triglyceride concentrations and lower neutrophil counts and serum Mn concentrations (all P < .05). No differences were found regarding other 5 trace elements in patients with versus without myosteatosis. The median serum Mn concentrations were 1.16 µg/L, and this population was categorized into high-Mn and low-Mn groups. The proportion of myosteatosis was significantly lower in high-Mn group than that in low-Mn group (8.1% vs 20.4%, P < .001). Univariable binary logistic regression indicated that low Mn was associated with myosteatosis (odds ratio, 2.906; 95% confidence interval, 1.424–5.932; P = .003) in the context of cirrhosis. This result was validated according to multivariable analysis by adjusting for confounding factors. In conclusion, low serum Mn can be predictive of myosteatosis, a novel muscular abnormality representing more clinical relevance and close relation to inferior outcomes among cirrhosis.

Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans.

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6-29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography-tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.

Hepatoprotective and cardioprotective effects of empagliflozin in spontaneously hypertensive rats fed a high-fat diet

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.

Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

Dry period length affects rumen adaptation in dairy cattle precalving and during the first weeks after calving

Omitting or shortening the dry period may result in a fairly constant ration throughout the transition period of dairy cows, reducing the need for adaptation of cow metabolism and rumen function to a new lactation. The objective of this study was to determine the effect of dry period length on rumen adaptation and cow metabolic state during the transition period. Twelve pregnant, rumen-cannulated Holstein Friesian dairy cows at the end of their first lactation were assigned to one of 3 treatments: a conventional (60 d), short (30 d) or no dry period (0 d). At dry-off, cows received a dry cow ration until calving. Lactating cows received a lactation ration. Cows were monitored from 8 wk before calving until 8 wk after calving for milk yield and dry matter intake (DMI). Rumen biopsies were taken from 3 locations in the rumen at 60, 40 and 10 d before calving and 3, 7, 14, 28 and 56 d after calving to assess papillae dimensions. Blood was sampled weekly from 3 wk before until 8 wk after calving, and liver biopsies were taken at wk -2, wk 2 and wk 4 relative to calving. Prepartum, DMI and milk yield were greater for cows with a short or no dry period, compared with cows with a conventional dry period. Postpartum, DMI was greater for cows with a short dry period compared with cows with a conventional dry period. Plasma glucose concentration was greater for cows without a dry period, compared with the other dry period lengths postpartum. Plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate, and liver triglyceride content, did not differ among dry period. Rumen papillae differed in size based on biopsy location, but there was no interaction between biopsy location and the effect of dry period length. Rumen papillae surface area for cows managed for a 30 d or 60 d dry period decreased toward calving. At 40 d prepartum, papillae surface area was greater for short and no dry period treatment compared with a conventional dry period. At 10 d prepartum, papillae surface area was greater for the no dry period treatment compared with both other treatments, and this difference was still present 3 d postpartum. Cows managed for a short dry period showed faster increase in papillae dimensions after calving compared with cows managed for a conventional dry period. From d 28 onwards, no differences in papillae surface area were observed. The faster rumen adaptation postpartum may be related to the increased DMI during the first weeks postpartum for cows managed for a short dry period. However, this did not result in improved metabolic status or milk yield. The results from the present study demonstrate that the dietary changes related to a conventional dry period length affected rumen papillae development, not only prepartum but also early postpartum. Further optimization of dry period length as well as dietary composition throughout the transition period may support cows in their adaptation to a new lactation.

Trophic transfer of micro- and nanoplastics and toxicity induced by long-term exposure of nanoplastics along the rotifer (Brachionus plicatilis)-marine medaka (Oryzias melastigma) food chain

Microplastics (MPs) and nanoplastics (NPs) are emerging pollutants in the ocean, but their transfer and toxicity along the food chains are unclear. In this study, a marine rotifer (Brachionus plicatilis)-marine medaka (Oryzias melastigma) food chain was constructed to evaluate the transfer of polystyrene MPs and NPs (70 nm, 500 nm, and 2 μm, 2000 μg/L) and toxicity of 70 nm PS-NPs (0, 20, 200, and 2000 μg/L) on marine medaka after long-term food chain exposure. The results showed that the amount of 70 nm NPs accumulated in marine medaka was 1.24 μg/mg, which was significantly higher than that of 500 nm NPs (0.87 μg/mg) and 2 μm MP (0.69 μg/mg). Long-term food chain exposure to NPs caused microflora dysbiosis, resulting in activation of toll-like receptor 4 (TLR4) pathway, which induced liver inflammation. Moreover, NPs food chain exposure increased liver and muscle tissue triglyceride and lactate content, but decreased the protein, sugar, and glycogen content. NPs food chain exposure impaired reproductive function and inhibited offspring early development, which might pose a threat to the sustainability of marine medaka population. Overall, the study revealed the transfer of MPs and NPs and the effects of NPs on marine medaka along the food chain.

Abomasal infusion of branched-chain amino acids or branched-chain keto-acids alter lactation performance and liver triglycerides in fresh cows

BackgroundDairy cows are at high risk of fatty liver disease in early lactation, but current preventative measures are not always effective. Cows with fatty liver have lower circulating branched-chain amino acid (BCAA) concentrations whereas cows with high circulating BCAA levels have low liver triglyceride (TG). Our objective was to determine the impact of BCAA and their corresponding ketoacids (branched-chain ketoacids, BCKA) on production performance and liver TG accumulation in Holstein cows in the first 3 weeks postpartum.MethodsThirty-six multiparous Holstein cows were used in a randomized block design experiment. Cows were abomasally infused for the first 21 d postpartum with solutions of 1) saline (CON, n = 12); 2) BCA (67 g valine, 50 g leucine, and 34 g isoleucine, n = 12); and 3) BCK (77 g 2-ketovaline calcium salt, 57 g 2-ketoleucine calcium salt, and 39 g 2-ketoisoleucine calcium salt, n = 12). All cows received the same diet. Treatment effects were determined using PROC GLIMMIX in SAS.ResultsNo differences were detected for body weight, body condition score, or dry matter intake averaged over the first 21 d postpartum. Cows receiving BCK had significantly lower liver TG concentrations compared to CON (6.60% vs. 4.77%, standard error of the mean (SEM) 0.49) during the first 3 weeks of lactation. Infusion of BCA increased milk yield (39.5 vs. 35.3 kg/d, SEM 1.8), milk fat yield (2.10 vs. 1.69 kg/d, SEM 0.08), and lactose yield (2.11 vs. 1.67 kg/d, SEM 0.07) compared with CON. Compared to CON, cows receiving BCA had lower plasma glucose (55.0 vs. 59.2 mg/dL, SEM 0.86) but higher β-hydroxybutyrate (9.17 vs. 6.00 mg/dL, SEM 0.80).ConclusionsOverall, BCAA supplementation in this study improved milk production, whereas BCKA supplementation reduced TG accumulation in the liver of fresh cows.Graphical

Ishimozuku (Sphaerotrichia firma) lipids containing fucoxanthin suppress fatty liver and improve short chain fatty acid production in obese model mice

Ishimozuku (Sphaerotrichia firma) is one species of edible brown algae in Japan. The lipids contain rich of fucoxanthin and n-3 unsaturated fatty acids. This study analyzed dietary Ishimozuku lipid components and the effects on fatty liver and intestinal metabolite component production in obese model mice. Fatty acid composition and fucoxanthin contents of Ishimozuku lipids were analyzed by gas chromatography (GC) and high performance liquid chromatography (HPLC) analysis. Ishimozuku lipids contained fucoxanthin about 44.71 ± 0.02 mg/g. KK-Ay mice were fed with high-fat diet (Control) and a high-fat diet + 0.5% Ishimozuku lipid diet (Ishimozuku) for 4 weeks. Liver triglyceride contents and serum triglyceride concentrations were significantly lower in the Ishimozuku group than in the Control group. Results show that acetyl-CoA carboxylase (ACC) and stearoyl-CoA desaturase (SCD-1) mRNA expression were suppressed in the livers of Ishimozuku group mice. Furthermore, short chain fatty acid amounts in the cecal contents were greater in the Ishimozuku group mice. These results suggest that dietary Ishimozuku lipid components suppress liver lipid accumulation. Results also indicate Ishimozuku lipid components improve the balance of the intestinal microflora, which is disturbed by a high fat diet, and which promotes short chain fatty acid accumulation in the intestine. That accumulation is related to lipid and glucose metabolism.