Hepatic lipid metabolism in adult rats using early weaning models: sex-related differences

AbstractNon-pharmacological early weaning (NPEW) induces liver damage in male progeny at adulthood; however, pharmacological early weaning (PEW) does not cause this dysfunction. To elucidate this difference in liver dysfunction between these two models and determine the phenotype of female offspring, de novo lipogenesis, β-oxidation, very low-density lipoprotein (VLDL) export, and gluconeogenesis in both sexes were investigated in the adult Wistar rats that were weaned after a normal period of lactation (control group) or early weaned either by restriction of access to the dams’ teats (NPEW group) or by reduction of dams’ milk production with bromocriptine (PEW group). The offspring received standard diet from weaning to euthanasia (PN180). NPEW males had higher plasma triglycerides and TyG index, liver triglycerides, and cholesterol by de novo lipogenesis, which leads to intracellular lipids accumulation. As expected, hepatic morphology was preserved in PEW males, but they showed increased liver triglycerides. The only molecular difference between PEW and NPEW males was in acetyl-CoA carboxylase-1 (ACC-1) and stearoyl-CoA desaturase-1 (SCD-1), which were lower in PEW animals. Both early weaning (EW) females had no changes in liver cholesterol and triglyceride contents, and the hepatic cytoarchitecture was preserved. The expression of microsomal triglyceride transfer protein was increased in both the female EW groups, which could constitute a protective factor. The changes in hepatic lipid metabolism in EW offspring were less marked in females. EW impacted in the hepatic cytoarchitecture only in NPEW males, which showed higher ACC-1 and SCD-1 when compared to the PEW group. As these enzymes are lipogenic, it could explain a worsened liver function in NPEW males.

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Effect of Central Corticotropin-Releasing Factor on Hepatic Lipid Metabolism and Inflammation-Related Gene Expression in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22083940 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3940

Author(s):

Yukiomi Nakade ◽

Rena Kitano ◽

Taeko Yamauchi ◽

Satoshi Kimoto ◽

Kazumasa Sakamoto ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

De Novo ◽

Corticotropin Releasing Factor ◽

De Novo Lipogenesis ◽

Control Group ◽

Mrna Levels ◽

Related Gene ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 μg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1β mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1β mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.

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Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways

Archives of Biological Sciences ◽

10.2298/abs190306023n ◽

2019 ◽

Vol 71 (3) ◽

pp. 417-424 ◽

Cited By ~ 2

Author(s):

Jelena Brkljacic ◽

Natasa Velickovic ◽

Ivana Elakovic ◽

Ana Teofilovic ◽

Danijela Vojnovic-Milutinovic ◽

...

Keyword(s):

Lipid Metabolism ◽

De Novo ◽

De Novo Lipogenesis ◽

Female Rats ◽

Acid Oxidation ◽

Hepatic Lipid Metabolism ◽

Male And Female ◽

Hepatic Lipid ◽

Male And Female Rats ◽

Dietary Fructose

An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41009]

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Transcriptome Analysis of the Effects of Fasting Caecotrophy on Hepatic Lipid Metabolism in New Zealand Rabbits

Animals ◽

10.3390/ani9090648 ◽

2019 ◽

Vol 9 (9) ◽

pp. 648 ◽

Cited By ~ 2

Author(s):

Wang ◽

Xu ◽

Sun ◽

Xue ◽

Sun ◽

...

Keyword(s):

Lipid Metabolism ◽

New Zealand ◽

Differentially Expressed Genes ◽

Liver Weight ◽

Differentially Expressed ◽

Control Group ◽

Feed Conversion ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Experimental Group

In order to investigate the effects of fasting caecotrophy on hepatic lipid metabolism in rabbits, 12 weaned female New Zealand white rabbits were randomly divided into (n = 6/group) a control and fasting caecotrophy group. Rabbits in the experimental group were treated with an Elizabeth circle to prevent them from eating their own soft feces for a 60-day period. Growth and blood biochemical indices, transcriptome sequencing and histology analysis of the liver were performed. Compared with the control group, final weight, weight gain, liver weight, growth rate and feed conversion ratio, all decreased in the experimental group (p < 0.05). RNA sequencing (RNA-seq) analysis revealed a total of 301.2 million raw reads (approximately 45.06 Gb of high-quality clean data) that were mapped to the rabbit genome. After a five-step filtering process, 14,964 genes were identified, including 444 differentially expressed genes (p < 0.05, foldchange ≥ 1). A number of differently expressed genes linked to lipid metabolism were further analyzed including CYP7A1, SREBP, ABCA1, GPAM, CYP3A1, RBP4 and RDH5. The KEGG (Kyoto Encyclopedia of Genes and Genomes) annotation of the differentially expressed genes indicated that main pathways affected were pentose and glucuronide interactions, starch and sucrose metabolism, retinol metabolism and PPAR signaling. Overall, the present study revealed that preventing caecotrophy reduced growth and altered lipid metabolism, both of which will help guide the development of new approaches for rabbits’ feeding and production. These data also provide a reference for studying the effects of soft feces in other small herbivores.

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Alcohol effects on hepatic lipid metabolism

The Journal of Lipid Research ◽

10.1194/jlr.r119000547 ◽

2020 ◽

Vol 61 (4) ◽

pp. 470-479 ◽

Cited By ~ 7

Author(s):

Sookyoung Jeon ◽

Rotonya Carr

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Hepatic Steatosis ◽

De Novo ◽

Lipid Synthesis ◽

Acid Oxidation ◽

Lipid Uptake ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.

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Silencing Retinoid X Receptor Alpha Expression Enhances Early-Stage Hepatitis B Virus Infection In Cell Cultures

Journal of Virology ◽

10.1128/jvi.01771-17 ◽

2018 ◽

Vol 92 (8) ◽

pp. e01771-17 ◽

Cited By ~ 17

Author(s):

Mei Song ◽

Yinyan Sun ◽

Ji Tian ◽

Wenhui He ◽

Guangwei Xu ◽

...

Keyword(s):

Lipid Metabolism ◽

Cell Cultures ◽

De Novo ◽

Early Stage ◽

Retinoid X Receptor ◽

Hbv Infection ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Receptor Alpha ◽

Retinoid X Receptor Alpha

ABSTRACTMultiple steps of the life cycle of hepatitis B virus (HBV) are known to be coupled to hepatic metabolism. However, the details of involvement of the hepatic metabolic milieu in HBV infection remain incompletely understood. Hepatic lipid metabolism is controlled by a complicated transcription factor network centered on retinoid X receptor alpha (RXRα). Here, we report that RXRα negatively regulates HBV infection at an early stage in cell cultures. The RXR-specific agonist bexarotene inhibits HBV in HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) (HepG2-NTCP), HepaRG cells, and primaryTupaiahepatocytes (PTHs); reducing RXRα expression significantly enhanced HBV infection in the cells. Transcriptome sequencing (RNA-seq) analysis of HepG2-NTCP cells with a disruptedRXRα gene revealed that reduced gene expression in arachidonic acid (AA)/eicosanoid biosynthesis pathways, including the AA synthases phospholipase A2 group IIA (PLA2G2A), is associated with increased HBV infection. Moreover, exogenous treatment of AA inhibits HBV infection in HepG2-NTCP cells. These data demonstrate that RXRα is an important cellular factor in modulating HBV infection and implicate the participation of AA/eicosanoid biosynthesis pathways in the regulation of HBV infection.IMPORTANCEUnderstanding how HBV infection is connected with hepatic lipid metabolism may provide new insights into virus infection and its pathogenesis. By a series of genetic studies in combination with transcriptome analysis and pharmacological assays, we here investigated the role of cellular retinoid X receptor alpha (RXRα), a crucial transcription factor for controlling hepatic lipid metabolism, inde novoHBV infection in cell cultures. We found that silencing of RXRα resulted in elevated HBV covalently closed circular DNA (cccDNA) formation and viral antigen production, while activation of RXRα reduced HBV infection efficiency. Our results also showed that silencing phospholipase A2 group IIA (PLA2G2A), a key enzyme of arachidonic acid (AA) synthases, enhanced HBV infection efficiency in HepG2-NTCP cells and that exogenous AA treatment reducedde novoHBV infection in the cells. These findings unveil RXRα as an important cellular factor in modulating HBV infection and may point to a new strategy for host-targeted therapies against HBV.

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Altered Hepatic Lipid Metabolism Contributes to Nonalcoholic Fatty Liver Disease in Leptin-Deficient Ob/Ob Mice

Journal of Obesity ◽

10.1155/2013/296537 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 36

Author(s):

James W. Perfield ◽

Laura C. Ortinau ◽

R. Taylor Pickering ◽

Meghan L. Ruebel ◽

Grace M. Meers ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

De Novo ◽

Hepatic Lipid Metabolism ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity, insulin resistance, and abnormal hepatic lipid metabolism; however, the precise regulation of these processes remains poorly understood. Here we examined genes and proteins involved in hepatic oxidation and lipogenesis in 14-week-old leptin-deficient Ob/Ob mice, a commonly studied model of obesity and hepatic steatosis. Obese Ob/Ob mice had increased fasting glucose, insulin, and calculated HOMA-IR as compared with lean wild-type (WT) mice. Ob/Ob mice also had greater liver weights, hepatic triglyceride (TG) content, and markers ofde novolipogenesis, including increased hepatic gene expression and protein content of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), as well as elevated gene expression of PPARγand SREBP-1c compared with WT mice. While hepatic mRNA levels for PGC-1α, PPARα, and TFAM were elevated in Ob/Ob mice, measures of mitochondrial function (β-HAD activity and complete (to CO2) and total mitochondrial palmitate oxidation) and mitochondrial OXPHOS protein subunits I, III, and V content were significantly reduced compared with WT animals. In summary, reduced hepatic mitochondrial content and function and an upregulation inde novolipogenesis contribute to obesity-associated NAFLD in the leptin-deficient Ob/Ob mouse.

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ULK1 Regulates Hepatic Lipid Metabolism via Autophagy Independent Mechanisms

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.617 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A303-A303

Author(s):

Young Do Koo ◽

Romilia Tatiana Castillo ◽

Antentor Othrell Hinton ◽

Evan Dale Abel

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

De Novo ◽

De Novo Lipogenesis ◽

Chow Diet ◽

Hepatic Lipid Metabolism ◽

Critical Pathway ◽

Hepatic Lipid ◽

Normal Chow

Abstract Non-alcoholic steatohepatitis (NASH), a major complication of obesity, diabetes, and metabolic syndrome has emerged as a leading cause of chronic liver disease and a risk factor for hepatocellular carcinoma. Autophagy is a critical pathway for the degradation of intracellular components by lysosomes. Established functions for autophagy in hepatic lipid metabolism and insulin sensitivity suggest a mechanistic link between altered autophagy and NASH. However, the interactions between insulin sensitivity, NASH, and autophagy are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. In this study, we observed that ULK1 may directly regulate insulin signaling and lipid metabolism via mechanisms that might involve modulation of AKT dephosphorylation. Surprisingly, silencing ULK1 did not significantly alter autophagy in hepatocytes despite impairing insulin-stimulated activation of AKT. To further elucidate the autophagy-independent role of ULK1 in hepatic lipid metabolism and insulin action, ULK1 liver-specific knock-out mice were generated. L-ULK1 KO mice exhibited impaired glucose tolerance and insulin resistance on a normal chow diet or 60% high-fat diet (HFD). In young mice (4 weeks after birth), the expression of genes that regulate de novo lipogenesis, such as FAS, SCD1, and SREBP1-c were induced in livers of L-ULK1KO mice even prior to the development of insulin resistance and obesity. Hepatomegaly and lipid accumulation developed in L-ULK1KO on normal chow and was exacerbated relative to wild type mice on a HFD. Serum concentrations of insulin, triglyceride, cholesterol, AST and ALT were significantly increased. In contrast, L-ULK2 KO mice were phenotypically normal. To identify putative novel ULK1 targets, we conducted a phospho-proteomics screen in a ULK1 deficient hepatocyte cell line. We identified a relatively small number of novel proteins whose phosphorylation levels were reduced by ULK1 deficiency. The identification of these targets supports autophagy-independent mechanisms of action of ULK1. Recently, we confirmed that NCOA3, one of the targets regulates hepatic lipid metabolism by interacting directly with ULK1. These data suggest that ULK-1 may regulate cellular targets that regulate hepatic lipid metabolism and insulin sensitivity.

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A New Strain of Christensenella minuta as a Potential Biotherapy for Obesity and Associated Metabolic Diseases

Cells ◽

10.3390/cells10040823 ◽

2021 ◽

Vol 10 (4) ◽

pp. 823

Author(s):

Wilfrid Mazier ◽

Katy Le Corf ◽

Ccori Martinez ◽

Héloïse Tudela ◽

Déborah Kissi ◽

...

Keyword(s):

Lipid Metabolism ◽

Gut Microbiota ◽

Metabolic Diseases ◽

De Novo ◽

De Novo Lipogenesis ◽

Hepatic Lipid Metabolism ◽

Metabolic Markers ◽

Shotgun Metagenomics ◽

Hepatic Lipid ◽

Diet Induced Obesity

Obesity is associated with gut microbiota dysbiosis, characterized by a high Firmicutes/Bacteroidetes ratio. Gut-dwelling bacteria of the Christensenellaceae family have been proposed to act as keystones of the human gut ecosystem and to prevent adipogenesis. The objectives of the present study were to demonstrate the antiobesity potential of a new strain of Christensenella minuta in preclinical models and explore related mechanisms of action. The antiobesity potential of C. minuta DSM33407 was assessed in a diet-induced obesity mouse model. Changes in hepatic lipid metabolism were explored using targeted transcriptomics. Effects on gut microbiota were further assessed in a humanized Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) model inoculated with obese fecal samples. Shotgun metagenomics was applied to study microbial community structures in both models. C. minuta DSM33407 protected from diet-induced obesity and regulated associated metabolic markers such as glycemia and leptin. It also regulated hepatic lipid metabolism through a strong inhibition of de novo lipogenesis and maintained gut epithelial integrity. In the humanized SHIME® model, these effects were associated with modulations of the intestinal microbiota characterized by a decreased Firmicutes/Bacteroidetes ratio. These data indicate that C. minuta DSM33407 is a convincing therapeutic candidate for the management of obesity and associated metabolic disorders.

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