Hepatic PKA inhibition accelerates the lipid accumulation in liver

Abstract Background/aims Liver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model. Methods A novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment. Results PKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding. Conclusions Reduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.

Download Full-text

Anti-Obesity Effects of Collagen Peptide Derived from Skate (Raja kenojei) Skin Through Regulation of Lipid Metabolism

Marine Drugs ◽

10.3390/md16090306 ◽

2018 ◽

Vol 16 (9) ◽

pp. 306 ◽

Cited By ~ 14

Author(s):

Minji Woo ◽

Yeong Song ◽

Keon-Hee Kang ◽

Jeong Noh

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Protein Expression ◽

The Body ◽

Chow Diet ◽

Dependent Manner ◽

Hepatic Lipid ◽

Collagen Peptide

This study investigated the anti-obesity effects of collagen peptide derived from skate skin on lipid metabolism in high-fat diet (HFD)-fed mice. All C57BL6/J male mice were fed a HFD with 60% kcal fat except for mice in the normal group which were fed a chow diet. The collagen-fed groups received collagen peptide (1050 Da) orally (100, 200, or 300 mg/kg body weight per day) by gavage, whereas the normal and control groups were given water (n = 9 per group). The body weight gain and visceral adipose tissue weight were lower in the collagen-fed groups than in the control group (p < 0.05). Plasma and hepatic lipid levels were significantly reduced by downregulating the hepatic protein expression levels for fatty acid synthesis (sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC)) and cholesterol synthesis (SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)) and upregulating those for β-oxidation (peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase 1 (CPT1)) and synthesis of bile acid (cytochrome P450 family 7 subfamily A member 1 (CYP7A1)) (p < 0.05). In the collagen-fed groups, the hepatic protein expression level of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK) and plasma adiponectin levels were higher, and the leptin level was lower (p < 0.05). Histological analysis revealed that collagen treatment suppressed hepatic lipid accumulation and reduced the lipid droplet size in the adipose tissue. These effects were increased in a dose-dependent manner. The findings indicated that skate collagen peptide has anti-obesity effects through suppression of fat accumulation and regulation of lipid metabolism.

Download Full-text

How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

Hepatology International ◽

10.1007/s12072-020-10121-2 ◽

2021 ◽

Vol 15 (1) ◽

pp. 21-35

Author(s):

Yana Geng ◽

Klaas Nico Faber ◽

Vincent E. de Meijer ◽

Hans Blokzijl ◽

Han Moshage

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Lipid Uptake ◽

Cellular Mechanisms ◽

Alcoholic Fatty Liver ◽

Lipid Species ◽

Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

Download Full-text

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽

10.3390/cells10051078 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1078

Author(s):

Debasish Roy ◽

Andrea Tedeschi

Keyword(s):

Nervous System ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

Axon Regeneration ◽

Axon Growth ◽

The Body ◽

Cns Repair ◽

Cord Injury ◽

Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

Download Full-text

Clinical and in Vivo Response Following Surgery or Surgery Plus Adjuvant Chemotherapy or Immunotherapy for Colorectal Carcinoma in a Rat Model

Journal of the Royal Society of Medicine ◽

10.1177/014107688307601007 ◽

1983 ◽

Vol 76 (10) ◽

pp. 833-840 ◽

Cited By ~ 6

Author(s):

A K House ◽

M A L Maley

Keyword(s):

Body Weight ◽

Adjuvant Chemotherapy ◽

Surgical Excision ◽

The Body ◽

Recurrent Tumour ◽

Mesenteric Node ◽

And Control ◽

Tumour Weight

Two cohorts of rats, 240 with colon cancer and 150 controls, were assessed clinically and immunologically for their response to tumour and its management which was either by surgical excision alone or by surgical excision combined with either adjuvant chemotherapy or immunotherapy. The histology and invasion characteristics were observed for similarity with those of human lesions. Metastases were found in liver, lymph nodes, the peritoneum or lungs in 27% of animals during follow up. Significantly fewer adjuvant-treated rats had metastases than those receiving surgery alone ( P < 0.05), and less total tumour weight was found in the adjuvant-treated rats at four ( P < 0.03) and six ( P < 0.001) weeks postoperatively. Animals in the adjuvant immunotherapy group survived longer than in either other group ( P < 0.001). The crude parameters of host response to tumour, body, spleen and mesenteric lymph node weight were recorded and the latter two indexed to body weight. The body weight of tumour and control rats increased significantly with time ( P < 0.04). The spleen and mesenteric node indices were significantly ( P < 0.04) greater in tumour than control rats and were varied by recurrent tumour growth and by the adjuvant treatment administered postoperatively.

Download Full-text

Significance of graded doses of aqueous seed extract of Moringa oleifera (L) on live body weight, gonadal, extragonadal dimensions and sperm reserves of Yankasa rams

Journal of Sustainable Veterinary and Allied Sciences ◽

10.54328/covm/josvas.2021.011 ◽

2021 ◽

pp. 33-40

Keyword(s):

Body Weight ◽

Moringa Oleifera ◽

Seed Extract ◽

The Body ◽

Control Group ◽

Live Body Weight ◽

And Control ◽

Standard Techniques ◽

Different Doses ◽

Apparently Healthy

The aim of the study was to investigate the effects of Moringa oleifera aqueous seed extract on live body weight, gonadal and extragonadal dimensions and sperm reserves of Yankasa rams. Twenty five apparently healthy Yankasa rams aged 1-2 years and weighing 19.0 ± 2.1 Kg were used for the study. The rams were randomly selected into five groups: A, B, C, D and E with five rams in each group as treatment and control groups respectively. Groups A - D were given oral dose of Moringa oleifera aqueous seed extract at a dose rate of 1000, 2000, 3000, 4000 (mg/kg), respectively while group E was given 10 ml/kg water orally, daily for five months. Live body weight, gonadal and extragonadal reserves were determined according to standard techniques. The results showed a significant increase in live body weight in the months of April to June among rams treated with different doses of Moringa oleifera aqueous seed extract compared with the control group. The control group showed no significant differences in the body weight, gonadal and extragonadal dimensions and sperm reserves. In conclusion, the treatment of Yankasa rams with Moringa oleifera aqueous seed extract increased live body weight, but had no significant effects on gonadal and extragonadal dimensions and sperm reserves in Yankasa rams. Therefore, it is recommended that M. oleifera aqueous seed extract can be used at doses of 2000mg/kg to 3000mg/kg in Yankasa rams for optimum gain in live body weight.

Download Full-text

Abstract 414: Ath28 Congenic Mice Confirm Atherosclerosis Modifying Gene on the Distal End of Chromosome 2

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.414 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Juying Han ◽

Jonathan D Smith

Keyword(s):

Body Weight ◽

Total Cholesterol ◽

Candidate Genes ◽

Aortic Root ◽

The Body ◽

Chow Diet ◽

Chromosome 2 ◽

Congenic Mice ◽

Cholesterol Levels ◽

Dd Mice

Objective: Strain intercrosses between apoE-deficient mice on the AKR (athero-resistant) and DBA/2 (athero-sensitive) strains identified the Ath28 quantitative trait locus (QTL) on the distal end of chromosome 2 (chr 2). We bred congenic mice on the DBA/2 background containing AKR alleles on chr 2 from 172.5 to 180 Mb in order to confirm the presence of atherosclerosis modifying genes in this region. Methods and Results: We used marker assisted backcrossing to generate DBA/2.AKR (chr 2) apoE-deficient congenic mice. High density genotyping using the MegaMuga array revealed that the AKR strain donated DNA on chr 2 from 171.5 Mb to the end of the chromosome, with the most distal marker tested at 180 Mb, while DBA/2 markers were found elsewhere in the genome. Mice heterozygote for the congenic interval were intercrossed to generate progeny homozygous for the AKR allele (AA) or the DBA/2 allele (DD). Female and male mice were fed a chow diet and sacrificed at 16 weeks of age. In the females, there was no effect on body weight; the total cholesterol levels trended 13% lower for the DD vs. AA mice (p=0.07); and, the HDL-C levels were 55% higher for the DD vs. AA mice (p=0.05). Despite having lower total cholesterol levels, the DD mice had 68% larger aortic root lesion areas (p=0.05, N=10 and 14 for AA and DD mice, respectively). In the males, the body weight was 12% higher in the DD vs. AA mice (p<0.01); the total cholesterol levels were similar in the DD and AA mice; and, the HDL-C levels were 73% higher for the DD vs. AA mice (p<0.05). The male DD mice had 27% larger aortic root lesion areas (NS), but we are adding more mice to this study to determine if this is significant (N=6 and 11 for AA and DD mice, respectively). Conclusions: Ath28 congenic mice confirm the presence of an atherosclerosis modifying gene on the distal end of chr 2 in chow-fed females. This interval in chr 2 contains over 100 genes. Our prior identification of missense variants between these strains, as well as transcriptomic and eQTL analyses have identified some candidate genes in this interval including Cstf1, Ctcfl, Zbp1, Ankrd60, Gnas, Cdh4, Ctsz, and Rae1 . Further functional genomic studies and creating mice with smaller congenic intervals will be needed in order to narrow the list of candidate genes for in vivo testing.

Download Full-text

Transplacental Toxicity and Carcinogenesis Studies in Rats with Hexamethylenetetramine

Tumori Journal ◽

10.1177/030089167005600602 ◽

1970 ◽

Vol 56 (6) ◽

pp. 325-334 ◽

Cited By ~ 16

Author(s):

Giuseppe Della Porta ◽

José R. Cabral ◽

Giorgio Parmiani

Keyword(s):

Drinking Water ◽

Body Weight ◽

Wistar Rats ◽

The Body ◽

Carcinogenic Activity ◽

Long Term Experiments ◽

Pregnancy And Lactation ◽

Successive Generations ◽

And Control

In a previous paper (Fd Cosmet. Toxicol., 6: 707–715, 1968) it was reported that hexamethylenetetramine (HMT) had no carcinogenic activity in long-term experiments in mice and rats. In the present study, 12 ♀ and 6 ♂ Wistar rats were given 1% HMT in the drinking water starting 2 weeks before mating. The females were kept under treatment during pregnancy and lactation. A similar untreated group of 12 ♀ and 6 ♂ served as control. Twelve treated females and eleven controls became pregnant and gave birth to 124 and 118 babies respectively; no malformations were noted. From these animals, 24 for each sex were continued on the 1% HMT up to the 20th week of age or were kept untreated. The body weight of treated animals was significantly lower than that of controls one, only up to the 9th week of age for the males and up to the 13th week for the females. At the end of the treatment both groups were sacrificed; the weight of organs was identical in the treated and control animals; there were no gross or histological pathology. In a second experiment, rats were given 1% HMT in the drinking water for 3 successive generations, up to the age of 40 weeks in the F1 and F2 groups and of 20 weeks for F3. The three groups were composed of 13 ♂ and 7 ♀, 15 ♂ and 11 ♀, 12 ♂ and 12 ♂, respectively. In addition, a group of 16 ♂ and 16 ♀ descendants of 2% HMT treated parents, were given 2% HMT for 50 weeks. A group of 48 ♂ and 48 ♀ served as untreated controls. All groups were kept under observation for over 2 years of age. No evidence of carcinogenicity was found in any of the HMT-treated groups.

Download Full-text

Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH)

British Journal Of Nutrition ◽

10.1017/s0007114515003621 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1745-1755 ◽

Cited By ~ 49

Author(s):

Cheng Jun Jin ◽

Cathrin Sellmann ◽

Anna Janina Engstler ◽

Doreen Ziegenhardt ◽

Ina Bergheim

Keyword(s):

Body Weight ◽

Tight Junction ◽

Liver Damage ◽

Sodium Butyrate ◽

The Body ◽

Tight Junction Protein ◽

Alcoholic Fatty Liver ◽

Protein Levels ◽

Alcoholic Steatohepatitis ◽

Junction Protein

AbstractOvernutrition, insulin resistance and an impaired intestinal barrier function are discussed as critical factors in the development of non-alcoholic fatty liver disease. Not only butyrate-producing probiotics as well as supplementation of sodium butyrate (SoB) have been suggested to bear protective effects on liver damage of various aetiologies. However, whether an oral consumption of SoB has a protective effect on Western-style diet (WSD)-induced non-alcoholic steatohepatitis (NASH) and if so molecular mechanism involved has not yet been determined. Eight-week-old C57BL/6J mice were pair-fed either a liquid control or WSD±0·6 g/kg body weight SoB. After 6 weeks, markers of liver damage, inflammation, toll-like receptor (TLR)-4 signalling, lipid peroxidation and glucose as well as lipid metabolism were determined in the liver tissue. Tight junction protein levels were determined in the duodenal tissue. SoB supplementation had no effects on the body weight gain or liver weight of WSD-fed mice, whereas liver steatosis and hepatic inflammation were significantly decreased (e.g. less inflammatory foci and neutrophils) when compared with mice fed only a WSD. Tight junction protein levels in duodenum, hepatic mRNA expression of TLR-4 and sterol regulatory element-binding protein 1c were altered similarly in both WSD groups when compared with controls, whereas protein levels of myeloid differentiation primary response gene 88, inducible nitric oxide synthase, 4-hydroxynonenal protein adducts and F4/80 macrophages were only significantly induced in livers of mice fed only the WSD. In summary, these data suggest that an oral supplementation of SoB protects mice from inflammation in the liver and thus from the development of WSD-induced NASH.

Download Full-text

The Effects of Triacylglycerol Structures on the Food Intake and Body Weight of Mice in a High-Fat Diet Setting

Current Developments in Nutrition ◽

10.1093/cdn/nzab055_026 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1216-1216

Author(s):

Xinge Hu

Keyword(s):

Body Weight ◽

Food Intake ◽

High Fat Diet ◽

Tissue Sample ◽

Body Weight Gain ◽

Diet Group ◽

The Body ◽

Lower Percentage ◽

Chow Diet ◽

High Fat

Abstract Objectives The dietary fat content plays an important role in the regulation of chronic metabolic diseases such as obesity and type 2 diabetes. Here, we tested the impacts of triacylglycerol structure on the body weight gain and food intake of mice in a high-fat diet (HFD) setting. Methods Male C57/BL6J mice at 6 weeks old were fed one of the following three diets for 6 weeks, Teklad Rodent Diet chow diet (number 8640), the chow diet containing 36% (w/w) 1,2-Dipalmitoyl-3-oleoylglycerol (PPO), or the chow diet containing 36% (w/w) 1,3-Dipalmitoyl-2-oleoylglycerol (POP). Each group contained 9 mice, and their food intake and BW were measured daily. The mice were euthanized after 6 weeks (12 weeks old) for tissue sample collection. Results Both high HFD groups had significantly higher BW gain and caloric intakes than the chow diet group. Mice fed the POP diet had a lower percentage of BW gain and consumed less accumulated calories than those fed the PPO diet, as well as a significantly lower liver to BW ratio. Since week 4, the body BW rate of the POP group started to be lower than that of the PPO diet group. Conclusions TAG structures in an HFD setting affect the BW gain rate and obesity in mice. The different structures of fat added to affect the food intake and BW gain differently in an HFD setting. In the future, we would like to compare the changes of the hepatic lipogenesis enzyme in these mice. This will help us to understand how the triacylglycerol structures in the diet affect lipid metabolism in mice. Funding Sources Internal.

Download Full-text

Effect of the Bacillus subtilis-based drug on the morphobiochemical and productive parameters of calves

E3S Web of Conferences ◽

10.1051/e3sconf/202127302011 ◽

2021 ◽

Vol 273 ◽

pp. 02011

Author(s):

Galina Molyanova ◽

Maxim Nogotkov ◽

Nelly Chigina

Keyword(s):

Body Weight ◽

Bacillus Subtilis ◽

Lipid Metabolism ◽

Average Daily Gain ◽

Dairy Farm ◽

The Body ◽

Control Group ◽

Production Experiment ◽

Daily Gain ◽

Experimental Group

The effect of Bisolbi drug based on Bacillus subtilis on the physiological, biochemical and productive parameters of calves was studied. The research and production experiment was carried out in a dairy farm “Kupinskoe” of Samara Region on 30 calves of the Holstein-Frisian breed. The drug increases the intensity of the anabolic processes in animals: the amount of total protein in blood serum of calves of the experimental group at 120 days of age was higher by 8.9% (p≤0.05), albumin 9.2% (p≤0.01), compared with control animals. The purpose of Bisolbi contributed to the increase in the intensity of carbohydrate-lipid metabolism: cholesterol was higher by 23% (p≤0.01), glucose 0.4 mmol/l (p≤0.05) in blood 120-day calves of the experimental group, relative to the data of the control group. It was found that the body weight of calves in the control group at 100 days of age was 105.23±2.11 kg, in the experimental group -108.6±2.19 kg. The average daily gain in the experimental group was significantly higher by 0.075 kg (p≤0.01). At 120 days of age, the body weight of the experimental calves was higher by 4.19 kg (p≤0.05), the average daily increase by 0.080 kg (p≤0.05), relative to the control animals.

Download Full-text