Hepatic Energy Metabolism Research Articles

Targeted proteomic analysis reveals that crocodile oil from Crocodylus siamensis may enhance hepatic energy metabolism in rats.

The liver is a key organ governing body energy metabolism. Dietary fats influence energy metabolism and mitochondrial functioning. Crocodile oil (CO) is rich in mono- and polyunsaturated fatty acids that contain natural anti-inflammatory and healing properties. Our study examined how CO affects the expressions of liver proteins involved in energy metabolism in rats. Twenty-one male Sprague Dawley rats were divided into three groups and underwent oral gavage with 3 ml/kg of sterile water (N group), CO (CO group), or palm oil (PO group) for 7 weeks. Body weight, energy intake, liver weight, liver indexes, blood lipid profiles, and liver-energy intermediates were measured. The liver proteome was analyzed using shotgun proteomics, and the functions and network interactions of several candidate proteins were predicted using the STITCH v.5.0 software. Body weights, energy intake, liver contents, and lipid profiles did not differ between the groups. However, hepatic oxaloacetate and malate levels were significantly higher in the CO group than in the PO group. Targeted proteomics reveals that 22 out of 1,790 unique proteins in the CO group were involved in energy-generating pathways, including the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS), and were correlated with the AMP-activated protein kinase signaling pathway. Cluster analysis of 59 differentially expressed proteins showed that OXPHOS-associated proteins were upregulated in the CO group and that three glycolytic metabolism-related proteins were downregulated in the CO group. CO may enhance hepatic energy metabolism by regulating the expressions of energy expenditure-related proteins.

Empagliflozin protects mice against diet-induced obesity, insulin resistance and hepatic steatosis

Aims/hypothesisSodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes, heart failure and chronic kidney disease. Their role in the prevention of diet-induced metabolic deteriorations, such as obesity, insulin resistance and fatty liver disease, has not been defined yet. In this study we set out to test whether empagliflozin prevents weight gain and metabolic dysfunction in a mouse model of diet-induced obesity and insulin resistance.MethodsC57Bl/6 mice were fed a western-type diet supplemented with empagliflozin (WDE) or without empagliflozin (WD) for 10 weeks. A standard control diet (CD) without or with empagliflozin (CDE) was used to control for diet-specific effects. Metabolic phenotyping included assessment of body weight, food and water intake, body composition, hepatic energy metabolism, skeletal muscle mitochondria and measurement of insulin sensitivity using hyperinsulinaemic–euglycaemic clamps.ResultsMice fed the WD were overweight, hyperglycaemic, hyperinsulinaemic and insulin resistant after 10 weeks. Supplementation of the WD with empagliflozin prevented these metabolic alterations. While water intake was significantly increased by empagliflozin supplementation, food intake was similar in WDE- and WD-fed mice. Adipose tissue depots measured by MRI were significantly smaller in WDE-fed mice than in WD-fed mice. Additionally, empagliflozin supplementation prevented significant steatosis found in WD-fed mice. Accordingly, hepatic insulin signalling was deteriorated in WD-fed mice but not in WDE-fed mice. Empagliflozin supplementation positively affected size and morphology of mitochondria in skeletal muscle in both CD- and WD-fed mice.Conclusions/interpretationEmpagliflozin protects mice from diet-induced weight gain, insulin resistance and hepatic steatosis in a preventative setting and improves muscle mitochondrial morphology independent of the type of diet.Graphical abstract

UPLC-QTOF/MS Metabolomics and Biochemical Assays Reveal Changes in Hepatic Nutrition and Energy Metabolism during Sexual Maturation in Female Rainbow Trout (Oncorhynchus mykiss).

Mobilization and repartition of nutrients and energy are prerequisites for the normal sexual maturity of broodstock. However, there are few studies on the mechanisms of hepatic nutrients and energy metabolism during sexual maturation in female rainbow trout (Oncorhynchus mykiss). This study investigated hepatic metabolite changes and explored the potential nutritional regulation mechanism between mature and immature female rainbow trout by combining UPLC-QTOF/MS metabolomics and biochemical assays. It was observed that hepatic biochemical assays differed considerably between the two groups, such as glucose, triglycerides, hexokinase, lipase, and aspartate aminotransferase. Liver metabolomics showed that various differential metabolites involved in amino acid and lipid metabolism markedly increased, suggesting the enhancement of lipid metabolism and amino acid anabolism in the liver provides the necessary material basis for ovarian development. Meanwhile, glycogen catabolism and glycolysis hold the key to maintaining organismal energy homeostasis with normal sexual maturation of female rainbow trout. Overall, the results from this study suggested that the liver undergoes drastic reprogramming of the metabolic profile in response to mobilization and repartition of nutrients and energy during the sexual maturation of female rainbow trout. This study further deepened the understanding of the reproductive biology of rainbow trout, and provided the theoretical basis and practical ramifications for nutritional requirements of breeding high-quality broodstock in the artificial propagation of rainbow trout.

Low levels of osteocalcin, but not CTX or P1NP, are associated with nonalcoholic hepatic steatosis and steatohepatitis

AimThe association of bone turnover with the incidence and progression of nonalcoholic fatty liver disease (NAFLD) is unclear. We aimed to evaluate serum levels of bone turnover markers in relation to NAFLD and nonalcoholic hepatic steatohepatitis (NASH). MethodsTwo cohorts were involved in our study. For the first cohort, 370 participants without NAFLD were retrospectively recruited and followed up for incident NAFLD according to ultrasound. For the second cohort, 562 subjects who underwent liver biopsy were included and grouped into non-NAFLD, non-NASH or NASH according to the NASH Clinical Research Network system. The bone turnover markers osteocalcin, C-terminal telopeptide (CTX) and N-terminal propeptide of type-1 procollagen (P1NP) were measured. ResultsBaseline osteocalcin was significantly lower in subjects who developed NAFLD (13.93 [11.03;16.39] versus 18.24 [15.45;22.47] ng/ml, P < 0.001), with a median of 26.4 months of follow-up. Low levels of osteocalcin, but not CTX or P1NP, was an independent predictor of incident NAFLD (OR 0.755 [95%CI 0.668; 0.855] P < 0.001). Moreover, the osteocalcin level was negatively associated with the degree of liver steatosis. Furthermore, subjects with NASH had significantly lower osteocalcin than non-NASH and non-NAFLD group (13.28 [10.49;16.59] versus 14.91 [12.45;18.09] versus 18.21 [15.04;22.05] ng/ml, all P < 0.001). A low osteocalcin level was an independent risk factor for NASH (OR for highest versus lowest quartile: 0.282 [0.147;0.543] P < 0.001). ConclusionLow level of osteocalcin, but not CTX or P1NP, was associated with NAFLD and NASH, indicating its potential role as an important endocrine regulator of hepatic energy metabolism.

Hyperbaric oxygen rapidly improves tissue-specific insulin sensitivity and mitochondrial capacity in humans with type 2 diabetes: a randomised placebo-controlled crossover trial

Aims/hypothesisHyperbaric oxygen (HBO) therapy may improve hyperglycaemia in humans with type 2 diabetes, but underlying mechanisms are unclear. Our objective was to examine the glucometabolic effects of HBO on whole-body glucose disposal in humans with type 2 diabetes.MethodsIn a randomised placebo-controlled crossover trial located at the German Diabetes Center, 12 male individuals with type 2 diabetes (age 18–75 years, BMI <35 kg/m2, HbA1c 42–75 mmol/mol [6–9%]), randomly allocated by one person, underwent 2-h HBO, once with 100% (240 kPa; HBO) and once with 21% oxygen (240 kPa; control, CON). Insulin sensitivity was assessed by hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose, hepatic and skeletal muscle energy metabolism were assessed by 1H/31P-magnetic resonance spectroscopy, while high-resolution respirometry measured skeletal muscle and white adipose tissue (WAT) mitochondrial capacity. All participants and people assessing the outcomes were blinded.ResultsHBO decreased fasting blood glucose by 19% and increased whole-body, hepatic and WAT insulin sensitivity about one-third (p<0.05 vs CON). Upon HBO, hepatic γ-ATP concentrations doubled, mitochondrial respiratory control doubled in skeletal muscle and tripled in WAT (p<0.05 vs CON). HBO increased myocellular insulin-stimulated serine-473/threonine-308 phosphorylation of Akt but decreased basal inhibitory serine-1101 phosphorylation of IRS-1 and endoplasmic reticulum stress (p<0.05 vs CON).Conclusions/interpretationHBO-mediated improvement of insulin sensitivity likely results from decreased endoplasmic reticulum stress and increased mitochondrial capacity, possibly leading to low-dose reactive oxygen species-mediated mitohormesis in humans with type 2 diabetes.Trial registrationClinicalTrials.gov NCT04219215FundingGerman Federal Ministry of Health, German Federal Ministry of Education and Research, North-Rhine Westfalia Ministry of Culture and Science, European-Regional-Development-Fund, German-Research-Foundation (DFG), Schmutzler StiftungGraphical abstract

PSVII-20 Hepatic Mrna Expression of Nutrient and Mitochondrial Energy Metabolism Genes in Beef Steers Selected for low or High Residual Feed Intake

Abstract We evaluated the mRNA expression of genes involved in hepatic fatty acid, amino acid, and mitochondrial energy metabolism in crossbred beef steers with divergent low and high residual feed intake (RFI). Low-RFI beef steers (n = 8; RFI = - 1.93 kg/d) and high-RFI beef steers (n = 8; RFI = + 2.01kg/d) were selected from a group of 56 growing crossbred beef steers (average BW = 261 ± 18.5 kg) after a 49-d performance testing period. At the end of the 49-d period, liver biopsies were collected from the low-RFI and high-RFI beef steers for RNA extraction and cDNA synthesis. The mRNA expression of 84 genes each related to fatty acid metabolism, amino acid metabolism, and mitochondrial energy metabolism were analyzed using pathway-focused PCR-based arrays. The mRNA expression of genes with absolute fold change (FC) ≥ 2.0 having false discovery rate-adjusted P-values (FDR) ≤ 0.05 were considered to be differentially expressed. Eight genes (CRAT, SLC27A5, SLC27A2, ACSBG2, ACADL, ACADSB, ACAA1, and ACAA2) involved fatty acid transport and β-oxidation were upregulated in low-RFI, compared with high-RFI steers. Hepatic mRNA expression of a gene encoding for aminoadipate aminotransferase, an enzyme related to lysine degradation, was downregulated (FC = -5.45, P = 0.01) in low-RFI steers, whereas those of methionine adenosyltransferase I and aspartate aminotransferase 2, which both link amino acid and lipid metabolism, were upregulated. Two mitochondrial energy metabolism genes (UQCRC1 and ATP5G1) involved in ATP synthesis via oxidative phosphorylation were upregulated in low-RFI beef steers, compared with high-RFI beef steers. The results of this study demonstrated that low-RFI beef steers exhibit upregulation of molecular mechanisms related to fatty acid transport, fatty acid β-oxidation, and mitochondrial ATP synthesis, which suggest that low-RFI beef steers have enhanced metabolic capacity to maximize capture of energy and nutrients from feeds consumed.

MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK/YAP pathway.

Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-β as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.

Liver dysfunction and energy storage mobilization in traíra, Hoplias malabaricus (Teleostei, Erythrinidae) induced by subchronic exposure to toxic cyanobacterial crude extract.

Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 μg MC-LR eq kg-1 for 30 days and, thereafter, the plasma, liver, and white muscle was sampled for analyses. Liver tissue lost cellular structure organization showing round hepatocytes, hyperemia, and biliary duct obstruction. At the ultrastructural level, the mitochondria and the endoplasmic reticulum exhibited disorganization. Direct and total bilirubin increased in plasma. In the liver, the activity of acid phosphatase (ACP) increased, and the aspartate aminotransferase (AST) decreased; AST increased in plasma. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were unchanged in the liver, muscle, and plasma. Glycogen stores and the energetic metabolites as glucose, lactate, and pyruvate decrease in the liver; pyruvate decreased in plasma and lactate decreased in muscle. Ammonia levels increased and protein concentration decreased in plasma. CE alters liver morphology by causing hepatocyte intracellular disorder, obstructive cholestasis, and dysfunction in the activity of key liver enzymes. The increasing energy demand implies glucose mobilization and metabolic adjustments maintaining protein preservation and lipid recruitment to supply the needs for detoxification allowing fish survival.

O161 Hepatic energy metabolism of dairy cows in grazing systems with or without environmental control during lactation

O161 Hepatic energy metabolism of dairy cows in grazing systems with or without environmental control during lactation

Mechanisms of regenerative preconditioning in pigs with subtotal hepatectomies.

Portal vein occlusion shortly before extended hepatic resections has hepatoprotective properties, but its molecular effects have not been elucidated. We characterized the impact of regenerative preconditioning by portal vein embolization (PVE) on hepatic energy metabolism and cytokine expression. About 90% hepatectomies were performed in normal pigs (Control) and in pigs that underwent a PVE 24 h before the surgery (n = 10/group). Blood biochemistry and coagulation, liver damage, liver function (ICG), hepatic content of adenine nucleotides, and hepatic expression of inflammatory mediators (RT-PCR and WB) were determined before the hepatectomy, 15 min, and 24 h later. All PVE and hepatectomies were successfully accomplished. The 90% hepatectomy resulted in: Immediate reduction of ATP, leading to persistent decreases of energy load and ATP/ADP ratio up to the 24-h time-point; and pro-inflammatory expression profile of cytokines in the remnant liver. Prior performance of PVE attenuated the bioenergetic alterations and prevented many of the changes in hepatic cytokine expression. Regenerative preconditioning by PVE improved hepatic energy metabolism and modulated inflammatory mediators in the remnant liver in pigs undergoing major hepatectomies, potentially contributing to its hepatoprotective effects.

Sex-dependent effect of triphenyl phosphate on hepatic energy metabolism at the intersection of diet pattern in pubertal mice

Triphenyl phosphate (TPhP) is mostly residual in fat-rich foodstuff and ingestion is the main route for adolescents’ exposure. As a typical metabolic disruptor, however, sex-specific effect of TPhP-high fat diet (HFD) co-exposure in adolescent remains unknown. This study revealed that HFD exacerbated systematic inflammation and insulin insensitivity in female mice at pubertal stage after exposure to 25 mg/kg TPhP or above. Notably, the pattern of sexual selective metabolic disruption caused by TPhP was irrespective of diet after examined mice both in HFD and normal diet feeding. Female mice favored the energy storage in forms of D-glucose 6-phosphate, D-fructose 6-phosphate and triglyceride. That was further supported by mRNA levels of key enzymes in glycolysis, gluconeogenesis, and lipid metabolism. Contrastingly, the elevation of the corresponding genes ensuing by the depleted metabolites were observed in males. In mechanistic investigation, we observed a declination of serum estrogen, a master of energy homeostasis, in both sexes, irrespective of diet. However, only male mice displayed estrogen-hypothalamus negative feedback, supporting by the upregulation of gonadotropin-releasing hormone. Rather than the well-recognized estrogen receptor α, hepatic G protein-coupled estrogen receptor manifested sexual dichotomy, which desensitized to estrogenic response only in females. Collectively, this study posited that females were more susceptible to store energy under TPhP-HFD than males during pubertal partially through estrogenic pathway.

Residual Feed Intake in Beef Cattle Is Associated With Differences in Hepatic mRNA Expression of Fatty Acid, Amino Acid, and Mitochondrial Energy Metabolism Genes

We evaluated the mRNA expression of genes involved in hepatic fatty acid, amino acid, and mitochondrial energy metabolism in crossbred beef steers with divergent low and high residual feed intake (RFI). Low-RFI beef steers (n = 8; RFI = - 1.93 kg/d) and high-RFI beef steers (n = 8; RFI = + 2.01kg/d) were selected from a group of 56 growing crossbred beef steers (average BW = 261 ± 18.5 kg) fed a high-forage total mixed ration after a 49-d performance testing period. At the end of the 49-d performance testing period, liver biopsies were collected from the low-RFI and high-RFI beef steers for RNA extraction and cDNA synthesis. The mRNA expression of 84 genes each related to fatty acid metabolism, amino acid metabolism, and mitochondrial energy metabolism were analyzed using pathway-focused PCR-based arrays. The mRNA expression of 8 genes (CRAT, SLC27A5, SLC27A2, ACSBG2, ACADL, ACADSB, ACAA1, and ACAA2) involved fatty acid transport and β-oxidation were upregulated (FC ≥ 2.0, FDR ≤ 0.05) in low-RFI, compared to high-RFI steers. Among those involved in amino acid metabolism, hepatic mRNA expression of a gene encoding for aminoadipate aminotransferase, an enzyme related to lysine degradation, was downregulated (FC = -5.45, FDR = 0.01) in low-RFI steers, whereas those of methionine adenosyltransferase I and aspartate aminotransferase 2, which both link amino acid and lipid metabolism, were upregulated (FC ≥ 2.0, FDR ≤ 0.05). Two mitochondrial energy metabolism genes (UQCRC1 and ATP5G1) involved in ATP synthesis via oxidative phosphorylation were upregulated (FC ≥ 2.0, FDR ≤ 0.05) in low-RFI beef steers, compared to high-RFI beef steers. The results of this study demonstrated that low-RFI beef steers exhibit upregulation of molecular mechanisms related to fatty acid transport, fatty acid β-oxidation, and mitochondrial ATP synthesis, which suggest that low-RFI beef steers have enhanced metabolic capacity to maximize capture of energy and nutrients from feeds consumed.

Metabolic adaptations in dairy cows of diverging Holstein strains under two feeding strategies

The aim of this work was to focus on the molecular mechanisms related to hepatic energy metabolism in Holstein-Friesian dairy cows of different genetic origin subjected to two nutritional strategies throughout lactation. Model 1: Multiparous Holstein-Friesian cows subjected to two feeding strategies. From 0 to 180 days in milk (DIM) the cows were fed a totally mixed ration (TMR) ad libitum (G0, without grazing) or grazed Festuca arundinacea or Medicago sativa and were supplemented with concentrate (G1, with grazing). From 180 to 250 days, all cows grazed Festuca arundinacea and were supplemented with a DTM. Model 2: Holstein cows of New Zealand (NZH) or North American (NAH) genetic origin subjected to two feeding strategies, maximum grazing (MaxP) where forage represented 67 % of the offered dry matter intake (70:30 direct grazing of Medicago sativa and Dactylis glomerata or Festuca arundinacea to conserved forage ratio) and the remaining 33 % of the dry matter intake was offered as concentrate, and the fixed pasture strategy (FixP) where grazing represented 32 % of the DMI offered and the remaining was offered as a TMR. For model 1 plasma and liver biopsies were collected at -14, 35, 60, 110, 180 and 250 DIM and for model 2 liver biopsies were taken at -14, 21, 100 and 180 dry matter intake with the objective to characterize the metabolic-endocrine profiles, gene expression of metabolic pathways, mitochondrial function, protein levels and post-translational modifications by western blot. Our results showed that there was a hepatic mitochondrial dysfunction during early lactation associated with lysine acetylation levels in mitochondrial proteins in cows subjected to grazing strategies which is later reinstated towards late mid-lactation. However, NAH cows in the MaxP strategy failed to recover their mitochondrial function during late mid-lactation and showed higher expression of genes associated with gluconeogenesis suggesting greater persistence than NZH cows.

Yogurt-derived Lactobacillus plantarum Q16 alleviated high-fat diet-induced non-alcoholic fatty liver disease in mice

Accumulating evidence revealed that some probiotics regulated lipid metabolism and alleviated diet-induced non-alcoholic fatty liver disease (NAFLD). This study mainly explored whether yogurt-derived Lactobacillus plantarum Q16 modulated lipid and energy metabolism, and suppressed microbial dysbiosis in high-fat diet (HFD)-fed mice. Results showed that oral administration of L. plantarum Q16 improved serum and hepatic lipid profile. Protein analysis showed that L. plantarum Q16 could reduce hepatic lipid content by reducing the expression of FAS, ACC, SCD-1, Srebp-1c and ATGL, but increasing expression levels of CPT-1α, PPAR-α and ATGL. Meanwhile, L. plantarum Q16 also improved hepatic energy metabolism by regulating FGF21/adiponectin/AMPKα/PGC-1α signaling pathway. Metagenomic analysis also discovered that L. plantarum Q16 increased species diversity and richness of intestinal microbiota, promoted proliferation of beneficial commensals and suppressed the growth of endotoxin-producing microorganisms in the colon of HFD-fed mice. Overall, L. plantarum Q16 protected against HFD-induced NAFLD by improving hepatic profile and regulating colonic microbiota composition.

Maternal dietary methionine restriction alters the expression of energy metabolism genes in the duckling liver

BackgroundIn mammals, the nutritional status experienced during embryonic development shapes key metabolic pathways and influences the health and phenotype of the future individual, a phenomenon known as nutritional programming. In farmed birds as well, the quantity and quality of feed offered to the dam can impact the phenotype of the offspring. We have previously reported that a 38% reduction in the intake of the methyl donor methionine in the diet of 30 female ducks during the growing and laying periods - from 10 to 51 weeks of age - reduced the body weight of their 180 mule ducklings compared to that of 190 ducklings from 30 control females. The maternal dietary methionine restriction also altered the hepatic energy metabolism studied in 30 of their ducklings. Thus, their plasma glucose and triglyceride concentrations were higher while their plasma free fatty acid level was lower than those measured in the plasma of 30 ducklings from the control group. The objective of this new study was to better understand how maternal dietary methionine restriction affected the livers of their newly hatched male and female ducklings by investigating the hepatic expression levels of 100 genes primarily targeting energy metabolism, amino acid transport, oxidative stress, apoptotic activity and susceptibility to liver injury.ResultsSixteen of the genes studied were differentially expressed between the ducklings from the two groups. Maternal dietary methionine restriction affected the mRNA levels of genes involved in different pathways related to energy metabolism such as glycolysis, lipogenesis or electron transport. Moreover, the mRNA levels of the nuclear receptors PPARGC1B, PPARG and RXRA were also affected.ConclusionsOur results show that the 38% reduction in methionine intake in the diet of female ducks during the growing and egg-laying periods impacted the liver transcriptome of their offspring, which may explain the previously observed differences in their liver energy metabolism. These changes in mRNA levels, together with the observed phenotypic data, suggest an early modulation in the establishment of metabolic pathways.

Effect of SLC16A1 on Hepatic Glucose Metabolism in Newborn and Post-Weaned Holstein Bulls.

Background: Patterns of liver energy metabolism significantly differ from birth to adult in cattle undergoing change of rumen rumination. However, the genes involve in hepatic energy metabolism during bovine development and how regulate are still unclear. Methods: In this study, 0-day-old newborn calves (0W) and 9-week-old weaned calves (9W) were used to investigate differences in liver glucose metabolism at these stages of calf development. We did this primarily through the quantitation of energy metabolism indicators, then sequencing the liver transcriptome for each group of claves. Results: The transcriptome results showed 979 differentially expressed genes (DEGs), enriched in animal organ development, catabolic process, transmembrane transport. SLC16A1 involved in that and was locked to investigate. We explored the effects of SLC16A1 on glucose and lactate flux in vitro. We identified and verified its target, miR-22-3p, through bioinformatics and luciferase reporter assays. Moreover, this study found that miR-22-3p decreased cell activity by negatively regulating the SLC16A1. Importantly, our result showed the insulin-induced SLC16A1 mRNA expression decreased, regulated by promoter activity rather than miR-22-3p. Conclusions: Our study illustrates the role of SLC16A1 in the liver mediated metabolism of developing calves. These data enrich our knowledge of the regulatory mechanisms of liver mediated glucose metabolism in developing cattle.

Characterizing the Therapeutic Potential of the Adropin‐GPR19 Signaling Pathway in MAFLD

Obesity is the second leading cause of preventable death in the United States, and serves as a fundamental risk factor in various pathologies including metabolic‐associated fatty liver disease (MAFLD). The cellular and molecular mechanisms that drive obesity‐related disease in different tissues are not fully elucidated, and this represents an impediment to the development of effective and efficient treatments. Adropin is a nutritionally regulated liver‐ and brain‐derived peptide hormone that modulates metabolic homeostasis in several tissues. Adropin levels are significantly reduced in obese human subjects, and this decrease is linked to increased adiposity, impaired glucose homeostasis, and liver injury. Recent reports show that MAFLD patients exhibit a marked decrease in serum adropin levels, however the functional significance of this is unknown. Various studies suggest that a class A orphan G‐coupled protein receptor, GPR19, mediates adropin signal transduction, therefore we hypothesized that GPR19 may be the putative cellular receptor that permits adropin function in the liver. To investigate this, we used a novel whole‐body GPR19 knockout mouse to perform a preliminary characterization of the effects of GPR19 depletion on hepatic and whole‐body physiology. Using in vivo metabolic approaches, we report that GPR19 KO mice exhibit glucose intolerance, altered hepatic energy metabolism, and histological liver injury. Together, these data suggest that GPR19 KO mice display pathogenic events that promote a MAFLD phenotype, indicating that GPR19 may be critical for the protective effects of adropin signaling in the liver. These findings further define the fundamental role of the adropin‐GPR19 signaling pathway in the regulation of metabolic homeostasis, and thus highlight a potential target for therapeutic interventions in MAFLD.

The first study on the effect of crocodile oil from Crocodylus siamensis on hepatic mitochondrial function for energy homeostasis in rats.

Background and Aim:Consumption of fatty acids (FA) can alter hepatic energy metabolism and mitochondrial function in the liver. Crocodile oil (CO) is rich in mono-and polyunsaturated FAs, which have natural anti-inflammatory and healing properties. In rat livers, we investigated the effect of CO on mitochondrial function for energy homeostasis.Materials and Methods:Twenty-one male Sprague-Dawley rats were divided into three groups at random. Group 1 rats were given sterile water (RO), Group 2 rats were given CO (3% v/w), and Group 3 rats were given palm oil (PO) (3% v/w). For 7 weeks, rats were given sterile water, CO, and PO orally. The researchers looked at body weight, food intake, liver weight, energy intake, blood lipid profiles, and mitochondria-targeted metabolites in the liver. The liver’s histopathology, mitochondrial architecture, and hydrolase domain containing 3 (HDHD3) protein expression in liver mitochondria were studied.Results:Body weight, liver weight, liver index, dietary energy intake, and serum lipid profiles were all unaffected by CO treatment. The CO group consumed significantly less food than the RO group. The CO group also had significantly higher levels of oxaloacetate and malate than the PO group. CO treatment significantly ameliorated hepatic steatosis, as evidenced by a greater decrease in the total surface area of lipid particles than PO treatment. CO administration preserved mitochondrial morphology in the liver by upregulating the energetic maintenance protein HDHD3. Furthermore, chemical-protein interactions revealed that HDHD3 was linked to the energy homeostatic pathway.Conclusion:CO may benefit liver function by preserving hepatic mitochondrial architecture and increasing energy metabolic activity.

Dietary lipid droplet structure in postnatal life improves hepatic energy and lipid metabolism in a mouse model for postnatal programming

Early-life diets may have a long-lasting impact on metabolic health. This study tested the hypothesis that an early-life diet with large, phospholipid-coated lipid droplets (Concept) induces sustained improvements of hepatic mitochondrial function and metabolism. Young C57BL/6j mice were fed Concept or control (CTRL) diet from postnatal day 15 (PN15) to PN42, followed by western style (WSD) or standard rodent diet (AIN) until PN98. Measurements comprised body composition, insulin resistance (HOMA-IR), tricarboxylic acid (TCA) cycle- and β-oxidation-related hepatic oxidative capacity using high-resolution respirometry, mitochondrial dynamics, mediators of insulin resistance (diacylglycerols, DAG) or ceramides) in subcellular compartments as well as systemic oxidative stress. Concept feeding increased TCA cycle-related respiration by 33% and mitochondrial fusion protein-1 by 65% at PN42 (both p 0.05). At PN98, CTRL, but not Concept, mice developed hyperinsulinemia (CTRL/AIN 0.22 ± 0.44 vs. CTRL/WSD 1.49 ± 0.53 nmol/l, p 0.05 and Concept/AIN 0.20 ± 0.38 vs. Concept/WSD 1.00 ± 0.29 nmol/l, n.s.) and insulin resistance after WSD (CTRL/AIN 107 ± 23 vs. CTRL/WSD 738 ± 284, p 0.05 and Concept/AIN 109 ± 24 vs. Concept/WSD 524 ± 157, n.s.). WSD-induced liver weight was 18% lower in adult Concept-fed mice and β-oxidation-related respiration was 69% higher (p 0.05; Concept/WSD vs. Concept/AIN) along with lower plasma lipid peroxides (CTRL/AIN 4.85 ± 0.28 vs. CTRL/WSD 5.73 ± 0.47 µmol/l, p 0.05 and Concept/AIN 4.49 ± 0.31 vs. Concept/WSD 4.42 ± 0.33 µmol/l, n.s.) and were in part protected from WSD-induced increase in hepatic cytosolic DAG C16:0/C18:1. Early-life feeding of Concept partly protected from WSD-induced insulin resistance and systemic oxidative stress, potentially via changes in specific DAG and mitochondrial function, highlighting the role of early life diets on metabolic health later in life.

Activating Effects of the Bioactive Compounds From Coffee By-Products on FGF21 Signaling Modulate Hepatic Mitochondrial Bioenergetics and Energy Metabolism in vitro.

Coffee by-products contain bioactive compounds that have been shown to have the capacity to modulate human metabolism. The goal of this study was to investigate the effects of the main bioactive compounds in coffee by-products and two aqueous extracts from the coffee husk and silverskin on the activation of fibroblast growth factor 21 (FGF21) signaling and the subsequent regulation of mitochondrial bioenergetics and lipid and glucose metabolism. HepG2 cells treated with palmitic acid (PA) were used in a non-alcoholic fatty liver disease (NAFLD) cell model. The bioactive compounds from coffee by-products (50 μmol L−1) and the aqueous extracts from the coffee silverskin and coffee husk (100 μg mL−1) increased ERK1/2 phosphorylation and the secretion of FGF21 (1.3 to 1.9-fold). Coffee by-products' bioactive compounds counteracted inflammation and PA-triggered lipotoxicity. Oxidative stress markers (ROS, mitochondrial superoxide, and NADPH oxidase) and the activity of antioxidant enzymes (superoxide dismutase and catalase) were modulated through the activation of Nrf2 signaling. Mitochondrial bioenergetics were regulated by enhancing respiration and ATP production via PGC-1α, and the expression of oxidative phosphorylation complexes increased. Coffee by-products' bioactive compounds decreased lipid accumulation (23–41%) and fatty acid synthase activity (32–65%) and triggered carnitine palmitoyltransferase-1 activity (1.3 to 1.7-fold) by activating AMPK and SREBP-1c pathways. The GLUT2 expression and glucose uptake were increased (58–111%), followed by a promoted glucokinase activity (55–122%), while glucose production and phosphoenolpyruvate carboxykinase activity were reduced due to IRS-1/Akt1 regulation. The bioactive compounds from coffee by-products, primarily chlorogenic and protocatechuic acids, could regulate hepatic mitochondrial function and lipid and glucose metabolism by activating FGF21 and related signaling cascades.