Hepatic Nutrient Research Articles

ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells

Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.

Modulation of PI3K/AKT/mTOR signaling pathway in the ovine liver and duodenum during early pregnancy

The liver and intestine play a critical role in nutrient absorption, storage, and metabolism. The aim of this study was to evaluate expression pattern of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signaling pathway that included PI3K, AKT1, mTOR, FoxO1, SREBP-1, PPARα, PTEN and FXR in the maternal liver and duodenum. Ovine livers and duodenums were sampled at day 16 of the estrous cycle, and at days 13, 16 and 25 of gestation, and RT-qPCR, western blot and immunohistochemistry analysis were used to detect mRNA and protein expression. The results showed that expression of PI3K, AKT1, p-mTOR, FoxO1, SREBP-1 and PTEN upregulated in the maternal liver, and PPARα upregulated in the duodenum. However, expression of FoxO1, SREBP-1 and PTEN in the duodenum downregulated during early pregnancy. In addition, expression levels of SREBP-1, PTEN and PPARα in the maternal liver, and PI3K in the duodenum peaked at day 13 of pregnancy. In addition, expression levels of PI3K, p-mTOR and FoxO1 in the liver, and AKT1 and p-mTOR in the duodenum peaked at day 16 of pregnancy. Nevertheless, expression levels of FXR both in the maternal liver duodenum downregulated at days 13 and 16 of pregnancy. In conclusion, early pregnancy regulated expression pattern of PI3K/AKT/mTOR signaling pathway in the ovine liver and duodenum in a pregnancy stage-specific and tissue-specific manner, which may be necessary for the adaptations in maternal hepatic nutrient metabolism and intestinal nutrient absorption early pregnancy.

Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. Following medical diagnosis of MASH, individuals were randomized to treatment (n= 16) or control (n= 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (p <0.05) and non-esterified fatty acid suppression (p= 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease. Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. NCT03151798.

Maternal nutrient metabolism in the liver during pregnancy.

The liver plays pivotal roles in nutrient metabolism, and correct hepatic adaptations are required in maternal nutrient metabolism during pregnancy. In this review, hepatic nutrient metabolism, including glucose metabolism, lipid and cholesterol metabolism, and protein and amino acid metabolism, is first addressed. In addition, recent progress on maternal hepatic adaptations in nutrient metabolism during pregnancy is discussed. Finally, the factors that regulate hepatic nutrient metabolism during pregnancy are highlighted, and the factors include follicle-stimulating hormone, estrogen, progesterone, insulin-like growth factor 1, prostaglandins fibroblast growth factor 21, serotonin, growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, melatonin, adrenal hormone, leptin, glucagon-like peptide-1, insulin glucagon and thyroid hormone. Our vision is that more attention should be paid to liver nutrient metabolism during pregnancy, which will be helpful for utilizing nutrient appropriately and efficiently, and avoiding liver diseases during pregnancy.

Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations. Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets. Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.

Balanced replacement of fish meal with Hermetia illucens meal allows efficient hepatic nutrient metabolism and increases fillet lipid quality in gilthead sea bream (Sparus aurata)

In the present study, gilthead sea bream (Sparus aurata) was reared using sustainable feeds containing insect meal from Hermetia illucens larvae. Proteomics and proton nuclear magnetic resonance-based metabolomics analysis were used to assess the metabolic impact of the tested feeds in sea bream liver, whereas the composition of muscle fillets was characterized by means of metabolomics and gas chromatography of fatty acid methyl esters. Including 10% of insect meal while correspondingly reducing fish meal did not substantially alter the metabolism of dietary nutrients, leading to small but significant effects solely on lauric acid content of sea bream fillets. Furthermore, a few alterations in some markers of immune response, such as leukocyte elastase inhibitor-like, granzyme B (G, H)-like, and two associated ortholog groups, serpin B and chymase, were found. In the fish group fed with insect meal, liver morphology analysis showed no structural damage or inflammation and a lower amount of hepatic lipid deposition and accumulation.

Data From Balanced replacement of fish meal with Hermetia illucens meal allows efficient hepatic nutrient metabolism and increased fillet lipid quality in gilthead sea bream (Sparus aurata)

Data From Balanced replacement of fish meal with Hermetia illucens meal allows efficient hepatic nutrient metabolism and increased fillet lipid quality in gilthead sea bream (Sparus aurata)

Liver Fatty Acid, Mineral, and Fat-Soluble Nutrients in Wild and Captive Greater Prairie-Chickens

Abstract We measured fatty acids, minerals, and fat-soluble nutrients in liver tissues from greater prairie-chickens Tympanuchus cupido pinnatus as an ecological dietary surrogate for endangered Attwater's prairie-chickens T. c. attwateri and investigated differences associated with captive (nonreleased captive raised; n = 4), wild (n = 12), and combination (released captive raised; n = 5) diets. In general, we found more variability across all fatty acids in samples from released captive-raised birds than in samples from either nonreleased captive-raised or wild birds. Polyunsaturated fatty acids were lowest in captive-raised birds. Regarding minerals, liver sodium values were uniquely lower in released captive-raised birds, and copper and manganese concentrations were lower for both released and nonreleased captive-raised birds. Of the carotenoids that we evaluated, β-carotene was lower in livers from captive-raised birds than in livers from wild prairie-chickens. Zeaxanthin was lowest in livers from birds that were captive raised but nonreleased. Differences in hepatic nutrient concentration among the three study groups may be directly correlated with dietary ingredients. Our results suggest possible management actions for improved nutrition of prairie-chickens in future release programs, such as further refinement of trace mineral and β-carotene content of captive commercial diets, the addition of supplemental feeds in release protocols that include an elevated polyunsaturated fatty acid profile, green plant materials that elevate β-carotene content, provision of trace mineralized salt sources at release sites, and timing releases to coincide with periods of high natural resource availability to better duplicate nutrient diversity.

Gonad indices, morphology and muscle fatty acid compositions of male and female golden mahseer (Tor putitora) sampled from lake Bhimtal (Himalaya) at different seasons of the year

Adult male and female golden mahseer (n = 10–12) were collected during summer, monsoon, pre-winter and winter for evaluating gonadal seasonality, condition factor (CF), viscera-hepatosomatic index (VHSI), hepatocyte density (HD) and muscle fatty acid (FA) profile. In summer and monsoon, all males, but only 67% and 71% of females, were spawning capable in respective seasons. In pre-winter, males were mostly in regressing, but females were in regenerating phases. In winter, 50% of males and 14% of females were in the early spawning capable phase. VHSI and HD, in males only, were respectively highest and lowest in winter, indicating their nutrient recovery starting in pre-winter and completing in winter. Seasonal muscle FA profile of females only was linked to gonadal status, where C20:1, C22:1, C18:3n-6, C18:3n-3, C20:4n-3, C22:6n-3, total n-3 and n-6 FAs were depleted in peak spawning seasons. Overall, it was found that their spawning peak falls in summer and monsoon, but few early and late spawners were detected in winter and pre-winter, respectively. Males and females exhibited a different reproduction-linked nutrient allocation pattern; hepatic nutrient dynamic was prominent in males, but muscle FA dynamic was pronounced in females. CF dynamic was similar in both sexes.

Dietary leucine supplementation improves growth performance, metabolic responses of liver via GCN2/ATF4, and insulin signaling pathways in largemouth bass (Micropterus salmoides).

An 8-week growth experiment was conducted to investigate the effects of dietary leucine on growth performance, body composition, and gene expression of hepatic nutrient metabolism in the largemouth bass (Micropterus salmoides). Six isonitrogenous (49.87%) diets with graded leucine levels (2.62, 3.07, 3.60, 3.87, 4.20, 4.71% of dry diet) were fed to triplicate groups with 20 juvenile fish (20.00 ± 0.13g). The results revealed that the specific growth rate (SGR) and weight gain (WG) increased significantly with increasing dietary leucine levels, reached their maximal value in the Leu-4.20% groups, and then decreased slightly. Although the feed conversion ratio (FCR) showed decreasing trends, no significant difference was detected. Leucine supplementation significantly improved the content of body protein and total plasma protein (TP). Additionally, a higher expression level of target of rapamycin (TOR) and ribosomal protein S6 (S6) mRNA was observed in the Leu-3.87% and Leu-4.20% diets, whereas the GCN2 (general control nonderepressible2 kinase) and AFT4 (activating transcription factor 4) mRNA expression levels were suppressed. The lipid content of the body was not influenced by leucine levels, whereas the content of total triglyceride (TG) first decreased significantly with increasing dietary leucine levels from 2.62 to 3.87% and then increased with increasing leucine levels (4.20% to 4.71%). The total cholesterol (TC) and low-density lipoproteins (LDL) trended in a similar direction but did not achieve statistical significance (P > 0.05). The expression of insulin receptor substrate 1 (IRS-1) was significantly elevated by dietary leucine levels, while protein kinase B (AKT) and phosphatidylinositol 3-kinase (PI3K) expression was inconsistently upregulated. Furthermore, leucine supplementation decreased plasma glucose and hepatic glycogen contents, and the expression levels of glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6pase) were significantly inhibited at 4.20% and 4.71% leucine diets. Analyses of the change in SGR and FCR using the quadratic regression model estimated that the optimum dietary leucine requirement of juvenile largemouth bass was 4.42% and 4.63% of the dry diet (8.86% and 9.28% of dietary protein), respectively.

Comparative assessment of egg and larval quality traits of progeny from wild-collected and captive-matured brooders of endangered golden mahseer, Tor putitora: A prelude to quality broodstock development and seed production

In this study, we assessed the differences in reproductive outputs (fertilization and hatching rates); egg quality (egg size increase during hardening, biochemical composition, carotenoid content, and characteristics of ovarian fluid); and larval performance traits (growth, microanatomical development, survival, starvation response, and critical thermal tolerance) of progeny from captive-matured and wild-collected golden mahseer brooders. Fertilization and hatching rates were significantly higher in wild-collected brooders than in captive broodstock. Captive brooder eggs were significantly larger in size and weight but had significantly lower energy/nutrient (total protein, glucose, and triglyceride) reserves and total carotenoids. On the contrary, ovarian fluid from captive females had significantly higher levels of total protein, glucose, and triglycerides, possibly indicating weaker egg membrane and nutrient leakage due to membrane damage or lysis. During water hardening, the cumulative weight increase due to a higher water uptake rate was significantly higher in the wild origin eggs than captive brooder eggs. CTmax of larvae obtained from captive-matured brooders was lower during the early developmental stages (15 dph), but became similar to the CTmax of wild brooder's larvae at 35 dph. On the other hand, CTmin of captive origin larvae was higher than their wild counterparts at all examined stages. There were no differences in starvation tolerance of larvae between the two brooder types. Histological observations revealed that the intestinal nutrient absorption and hepatic nutrient accumulating efficiency during the early developmental stages was relatively lower in captive origin larvae, corresponding to the comparative growth metrics observed until 35 dph. Also, the survival percentage at 90 dph was lower in the larvae of captive brooders than their wild counterparts. Collectively, these findings indicate potential areas for improvement in the captive broodstock management of the endangered cyprinid, golden mahseer.

Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagAGTP mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from RagAGTP mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.

Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

BackgroundMethionine (Met) supply during late-pregnancy enhances fetal development in utero and leads to greater rates of growth during the neonatal period. Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves (n = 6/group) born to Holstein cows fed a control or the control plus ethyl-cellulose rumen-protected Met for the last 28 days prepartum were used for DNA methylation, transcriptome, metabolome, proteome, and one-carbon metabolism enzyme activities.ResultsAlthough greater withers and hip height at birth in Met calves indicated better development in utero, there were no differences in plasma systemic physiological indicators. RNA-seq along with bioinformatics and transcription factor regulator analyses revealed broad alterations in ‘Glucose metabolism’, ‘Lipid metabolism, ‘Glutathione’, and ‘Immune System’ metabolism due to enhanced maternal Met supply. Greater insulin sensitivity assessed via proteomics, and efficiency of transsulfuration pathway activity suggested beneficial effects on nutrient metabolism and metabolic-related stress. Maternal Met supply contributed to greater phosphatidylcholine synthesis in calf liver, with a role in very low density lipoprotein secretion as a mechanism to balance metabolic fates of fatty acids arising from the diet or adipose-depot lipolysis. Despite a lack of effect on hepatic amino acid (AA) transport, a reduction in metabolism of essential AA within the liver indicated an AA ‘sparing effect’ induced by maternal Met.ConclusionsDespite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

SummaryHypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.

Effects of glyphosate residues and different concentrate feed proportions in dairy cow rations on hepatic gene expression, liver histology and biochemical blood parameters.

Glyphosate (GLY) is worldwide one of the most used active substances in non-selective herbicides. Although livestock might be orally exposed via GLY-contaminated feedstuffs, not much is known about possible hepatotoxic effects of GLY. As hepatic xenobiotic and nutrient metabolism are interlinked, toxic effects of GLY residues might be influenced by hepatic nutrient supply. Therefore, a feeding trial with lactating dairy cows was conducted to investigate effects of GLY-contaminated feedstuffs and different concentrate feed proportions (CFP) in the diets as tool for varying nutrient supply to the liver. For this, 61 German Holstein cows (207 ± 49 days in milk; mean ± standard deviation) were either fed a GLY-contaminated total mixed ration (TMR, GLY groups, mean GLY intake 122.7 μg/kg body weight/day) or control TMR (CON groups, mean GLY intake 1.2 μg/kg body weight/day) for 16 weeks. Additionally, both groups were further split into subgroups fed a lower (LC, 30% on dry matter basis) or higher (HC, 60% on dry matter basis) CFP resulting in groups CONHC (n = 16), CONLC (n = 16), GLYHC (n = 15), GLYLC (n = 14). Blood parameters aspartate aminotransferase, γ-glutamyltransferase, glutamate dehydrogenase, cholesterol, triglyceride, total protein, calcium, phosphorus, acetic acid and urea and histopathological evaluation were not influenced by GLY, whereas all mentioned parameters were at least affected by time, CFP or an interactive manner between time and CFP. Total bilirubin blood concentration was significantly influenced by an interaction between GLY and CFP with temporarily elevated concentrations in GLYHC, whereas the biological relevance remained unclear. Gene expression analysis indicated 167 CFP-responsive genes, while seven genes showed altered expression in GLY groups compared to CON groups. Since expression changes of GLY-responsive genes were low and liver-related blood parameters changed either not at all or only slightly, the tested GLY formulation was considered to have no toxic effects on the liver of dairy cows.

Changes to hepatic nutrient dynamics and energetics in rainbow trout (Oncorhynchus mykiss) following exposure to and recovery from hydraulic fracturing flowback and produced water

Hydraulic fracturing flowback and produced water (FPW) is a highly complex and heterogenous wastewater by-product of hydraulic fracturing practices. To date, no research has examined how FPW exposure to freshwater biota may affect energetic homeostasis following subsequent induction of detoxification processes. Rainbow trout (Oncorhynchus mykiss) were acutely exposed for 48 h to either 2.5% or 7.5% FPW, and hepatic metabolism was assessed either immediately or following a 3-week recovery period. Induction of xenobiotic metabolism was observed with an 8.8-fold increase in ethoxyresorufin-O-deethylase (EROD) activity after 48 h exposure to 7.5% FPW, alongside a 10.3-fold increase in the mRNA abundance of cyp1a, both of which returned to basal level after three weeks. Glucose uptake capacity was elevated by 6.8- and 12.9-fold following 2.5% and 7.5% FPW exposure, respectively, while alanine uptake was variable. Activity measurements and mRNA abundance of key enzymes involved in hepatic metabolism indicated that aerobic metabolism was maintained with exposure, as was glycolysis. Gluconeogenesis, as measured by phosphoenolpyruvate carboxykinase (PEPCK) activity, decreased by ~30% 48 h following 2.5% FPW exposure and ~20% 3 weeks after 7.5% FPW exposure. The abundance of pepck mRNA activity followed similar, yet non-significant, trends. Finally, a delayed increase in amino acid catabolism was observed, as glutamate dehydrogenase (GDH) activity was increased 2-fold in 7.5% FPW exposed fish when compared to saline control fish at the 3-week time point. We provide evidence to suggest that although hepatic metabolism is altered following acute FPW exposure, metabolic homeostasis generally returns 3-weeks post-exposure.

Triphenyl phosphate causes a sexually dimorphic metabolism dysfunction associated with disordered adiponectin receptors in pubertal mice

The potential for triphenyl phosphate (TPhP) caused metabolic dysfunction has been documented. However, the relative mechanism of sexual dimorphic disruption on metabolism induced by TPhP remains unclear. Herein, we observed the insulin-sensitizing hormone (adiponectin) was inhibited in female serum while stimulated in males after oral administration of TPhP. Correspondingly, we found a high index of HOMA-IR in females. The primary receptors of adiponectin (AdipoR1 and AdipoR2) and the downstream: phosphorylation of AKT (pAKT) and PPAR⍺ signaling was attenuated in female liver. The disordered adiponectin/AdipoR signaling reduced hepatic glucose glycolysis and induced gluconeogenesis and finally led to the glucose intolerance in females. Also, the aberrant fatty acid β-oxidation and hepatic triacylglyceride (TG) deposition were found in female liver. Comparably, TPhP upregulated the AdipoR 1/2 and induced the downstream (pAMPK and PPAR⍺ signaling) in males. Thus, the serum glucose and hepatic TG level remained normal. However, modulation on AdipoR1/R2 and the genes related to glucose and lipid disposal in skeletal muscle has no gender-specific effect. Our research firstly revealed TPhP-induced hepatic nutrient metabolism was partially mediated by the adiponectin/AdipoR pathway in sexual-dependent manner during pubertal.

Dietary management of liver disorders

The liver is responsible for many important functions, including metabolism of ingested nutrients and toxins, and production of plasma proteins, clotting factors and bile salts. When the liver is diseased or damaged, dietary therapy is beneficial in preventing further damage; supporting hepatic repair and liver function; and decreasing signs of hepatic encephalopathy. The nutritional status of patients with liver disease is often compromised by anorexia; nutrient malassimilation due to portal hypertension and cirrhosis; and decreased hepatic nutrient synthesis or storage capacity. Appetite and the amounts of protein, carbohydrates, fats, vitamins and minerals should all be considered. Previously, reduced dietary protein was often recommended; however, reducing dietary protein concentrations in all animals with liver disease is not appropriate. Nutraceuticals may have a beneficial effect in some cases. Nutritional support specifically for feline hepatic lipidosis, copper associated liver disease and hepatic encephalopathy are discussed.

Tryptophan restriction partially recapitulates the age-dependent effects of total amino acid restriction on energy balance in diet-induced obese rats

Moderate dietary protein restriction promotes hyperphagia and thermogenesis; however, little is known of whether these responses are due to restriction of the essential amino acids tryptophan and histidine. Here, we determined whether restriction of tryptophan and histidine alone recapitulate the effects of total amino acid restriction on energy balance, and whether the metabolic responses are age-dependent. We fed young (12 weeks old) and older (29 weeks old) diet-induced obese rats with one of four high-fat diets: control (CON, 100% amino acid requirement), total amino acid restriction (TAA, 67% amino acid restriction), tryptophan restriction (TRP, 67% tryptophan restriction) or histidine restriction (HIS, 67% histidine restriction) for 21 days. Energy balance, hormones, and key markers of hepatic nutrient sensing and brown adipose thermogenesis were measured. We found that TAA increased food intake in both young and older rats, with TRP, but not HIS, transiently simulating the hyperphagia. TAA promoted sympathetically mediated increase in energy expenditure in young rats partly through increased β2-adrenergic and FGF21 signaling in brown fat; TRP partially emulated these responses. TRP and HIS transiently increased fat mass in young rats, and TAA promoted adiposity in older rats. TAA, TRP and HIS increased postprandial FGF21 concentrations in older rats. TAA induced age-dependent differential changes in markers of hepatic amino acid sensing; TRP and HIS partially mimicked these responses. Collectively, restriction of tryptophan, but not histidine, partially recapitulated the age-dependent metabolic effects of total amino acid restriction, in concert with distinct changes in hepatic amino acid sensing and signaling mechanisms.

Hepatic mitochondrial function in Hereford steers with divergent residual feed intake phenotypes1

Variations in phenotypic expression of feed efficiency could be associated with differences or inefficiencies in mitochondria function due to its impact on energy expenditure. The aim of this study was to determine hepatic mitochondrial density and function in terms of respiration, gene and protein expression, and enzyme activity of mitochondrial respiratory complex proteins, in steers of divergent residual feed intake (RFI) phenotypes. Hereford steers (n = 111 and n = 122 for year 1 and 2, respectively) were evaluated in postweaning 70 d standard test for RFI. Forty-six steers exhibiting the greatest (n = 9 and 16 for year 1 and 2; high-RFI) and the lowest (n = 9 and 12 for year 1 and 2; low-RFI) RFI values were selected for this study. After the test, steers were managed together until slaughter under grazing conditions until they reached the slaughter body weight. At slaughter, hepatic samples (biopsies) were obtained. Tissue respiration was evaluated using high-resolution respirometry methods. Data were analyzed using a mixed model that included RFI group as fixed effect and slaughter date and year as a random effect using PROC MIXED of SAS. RFI and dry matter intake were different (P < 0.001) between low and high-RFI groups of year 1 and year 2. Basal respiration and maximum respiratory rate were greater (P ≤ 0.04) for low than high-RFI steers when complex II substrates (succinate) were supplied. However, when Complex I substrates (glutamate/malate) were used maximum respiratory capacity tended to be greater (P < 0.09) for low vs. high-RFI steers. Low-RFI steers presented greater mitochondria density markers (greater (P < 0.05) citrate synthase (CS) activity and tended (P ≤ 0.08) to have greater CS mRNA and mtDNA:nDNA ratio) than high-RFI steers. Hepatic expression SDHA, UQCRC1, and CYC1 mRNA was greater (P ≤ 0.02) and expression of NDUFA4, NDUFA13, SDHD, UQCRH, and ATP5E mRNA tended (P ≤ 0.10) to be greater in low than high-RFI steers. Hepatic SDHA protein expression tended (P < 0.08) to be greater while succinate dehydrogenase activity was greater (P = 0.04) and NADH dehydrogenase activity was greater (P = 0.03) for low than high-RFI steers. High-efficiency steers (low-RFI) probably had greater efficiency in hepatic nutrient metabolism, which was strongly associated with greater hepatic mitochondrial density and functioning, mainly of mitochondrial complex II.