Carnitine Palmitoyltransferase 1 Regulates Prostate Cancer Growth under Hypoxia

Hypoxia and hypoxia-related biomarkers are the major determinants of prostate cancer (PCa) aggressiveness. Therefore, a better understanding of molecular players involved in PCa cell survival under hypoxia could offer novel therapeutic targets. We previously reported a central role of mitochondrial protein carnitine palmitoyltransferase (CPT1A) in PCa progression, but its role in regulating PCa survival under hypoxia remains unknown. Here, we employed PCa cells (22Rv1 and MDA-PCa-2b) with knockdown or overexpression of CPT1A and assessed their survival under hypoxia, both in cell culture and in vivo models. The results showed that CPT1A knockdown in PCa cells significantly reduced their viability, clonogenicity, and sphere formation under hypoxia, while its overexpression increased their proliferation, clonogenicity, and sphere formation. In nude mice, 22Rv1 xenografts with CPT1A knockdown grew significantly slower compared to vector control cells (~59% reduction in tumor volume at day 29). On the contrary, CPT1A-overexpressing 22Rv1 xenografts showed higher tumor growth compared to vector control cells (~58% higher tumor volume at day 40). Pathological analyses revealed lesser necrotic areas in CPT1A knockdown tumors and higher necrotic areas in CPT1A overexpressing tumors. Immunofluorescence analysis of tumors showed that CPT1A knockdown strongly compromised the hypoxic areas (pimonidazole+), while CPT1A overexpression resulted in more hypoxia areas with strong expression of proliferation biomarkers (Ki67 and cyclin D1). Finally, IHC analysis of tumors revealed a significant decrease in VEGF or VEGF-D expression but without significant changes in biomarkers associated with microvessel density. These results suggest that CPT1A regulates PCa survival in hypoxic conditions and might contribute to their aggressiveness.

Ginger (Zingiber officinale) Attenuates Obesity and Adipose Tissue Remodeling in High-Fat Diet-Fed C57BL/6 Mice

Obesity is characterized by excessive fat accumulation in adipose tissue, which is an active endocrine organ regulating energy metabolism. Ginger (Zingiber officinale) is known to have antioxidant, anti-inflammatory, and antiobesity effects, but the role of ginger in modulating adipocyte metabolism is largely unknown. In this study, we hypothesized that ginger supplementation inhibits high-fat (HF)-diet-mediated obesity. C57BL/6 male mice were randomly assigned to three diets for 7 weeks: low fat (LF, 16% kcal from fat), HF (HF, 60% kcal from fat), or HF with 5% ginger powder in diet (HF + G). The HF diet increased body weight (BW) and BW gain, as well as fasting glucose, total cholesterol, and hepatic lipid levels, compared to the LF diet-fed group. Ginger supplementation significantly improved HF-diet-induced BW gain, hyperglycemia, hypercholesterolemia, and hepatic steatosis without altering food intake. Next, we investigated whether ginger modulates adipocyte remodeling. HF-mediated adipocyte hypertrophy with increased lipogenic levels was significantly improved by ginger supplementation. Furthermore, the HF+G group showed high levels of the fatty-acid oxidation gene, carnitine palmitoyltransferase 1 (CPT1), which was accompanied by a reduction in adipocyte inflammatory gene expression. Taken together, our work demonstrated that ginger supplementation attenuated HF-diet-mediated obesity and adipocyte remodeling in C57BL/6 mice.

Carnitine Palmitoyltranferase Type 1 Deficiency: A Case Report of Fatty Acid Oxidation Disorder Encephalopathy

Background: Carnitine palmitoyltransferase-1 (CPT-1) deficiency is a rare autosomal recessive disorder of mitochondrial long-chain fatty acid oxidation with fewer than 30 case reports. Case report: A 30-month-old child with fever and loss of consciousness was referred to our hospital. She had symptoms of colds for three days that were treated, but she had anorexia.Her abdomen was soft and hepatomegaly 5 cm below the edge of the rib was detected. According to a neurological consultation, with the probability of a seizure, the patient beganto receive levetiracetam. The patient was treated with sodium benzoate due to her decreased level of consciousness and increased blood ammonia (300). In the acylcarnitine profile, mildlyelevated levels of single acylcarnitine were seen to confirm the diagnosis of CPT-1 deficiency. Conclusions: CPT-1 deficiency is a rare autosomal recessive defect of mitochondrial longchain fatty acid oxidation that presents as an acute “Reye-like” hepatic encephalopathy andnon-ketotic hypoglycemia, developmental delay, and hepatomegaly.

High Rumen-Degradable Starch Diet Promotes Hepatic Lipolysis and Disrupts Enterohepatic Circulation of Bile Acids in Dairy Goats

ABSTRACT Background High rumen-degradable starch (RDS) diets decrease milk fat. The increase of LPS in plasma associated with increased RDS impairs liver function, immune response and lipid metabolism, which depress the precursors for milk fat. Objective This study investigated the mechanism of depression of milk fat precursors in the liver and small intestine of dairy goats fed different RDS diets. Method Eighteen Guanzhong lactating goats (second lactation, 45.8 ± 1.54 kg) and 6 ruminally cannulated dairy goats (aged 2–3 y, 54.0 ± 2.40 kg) were fed 3 different diets with low dietary RDS concentrations of 20.52% (LRDS), medium RDS of 22.15% (MRDS), and high RDS of 24.88% (HRDS) for 36 and 21 d, respectively, in experiments 1 and 2. The liver metabolites and jejunal microbiota in experiment 1 and LPS concentrations in rumen fluid and plasma in experiment 2 were measured. One-way ANOVA was used to analyze the biochemical parameters and mRNA or protein expression. The MIXED procedure was used to analyze LPS concentrations. Results In experiment 1, the HRDS diet showed increased activity of alkaline phosphatase (27.4 to 41.4 U/L) in plasma (P < 0.05) compared with LRDS treatment. The HRDS diet significantly increased the hepatic concentrations of l-carnitine (129%), l-palmitoylcarnitine (306%), taurochenodeoxycholate (856%), and taurodeoxycholic acid (588%) in liver (variable importance in the projection > 1, P < 0.10) compared with the LRDS treatment. Goats fed the HRDS diet had 33.6% greater liver protein expression of carnitine palmitoyltransferase-1 (P < 0.05), and greater relative abundance of Firmicutes and Ruminococcus 2 in the jejunal content (linear discriminant analysis > 2.0, P < 0.05) than did goats fed LRDS diet. In experiment 2, goats fed the HRDS diet had greater LPS concentrations in rumen fluid (7.57 to 13.6 kEU/mL) and plasma (0.037 to 0.179 EU/mL) (P < 0.05) than did goats fed LRDS diet. Conclusions Feeding the HRDS diet promoted hepatic lipid β-oxidation and disrupted phospholipid and bile acids metabolisms in liver, thereby reducing the supply of lipogenic precursors to the mammary gland in dairy goats.

Ecklonia stolonifera Extract Suppresses Lipid Accumulation by Promoting Lipolysis and Adipose Browning in High-Fat Diet-Induced Obese Male Mice

Obesity develops due to an energy imbalance and manifests as the storage of excess triglyceride (TG) in white adipose tissue (WAT). Recent studies have determined that edible natural materials can reduce lipid accumulation and promote browning in WAT. We aimed to determine whether Ecklonia stolonifera extract (ESE) would increase the energy expenditure in high-fat diet (HFD)-induced obese mice and 3T3-L1 cells by upregulating lipolysis and browning. ESE is an edible brown marine alga that belongs to the family Laminariaceae and contains dieckol, a phlorotannin. We report that ESE inhibits body mass gain by regulating the expression of proteins involved in adipogenesis and lipogenesis. In addition, ESE activates protein kinase A (PKA) and increases the expression of lipolytic enzymes including adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and monoacylglycerol lipase (MGL) and also thermogenic genes, such as carnitine palmitoyltransferase 1 (CPT1), PR domain-containing 16 (PRDM16), and uncoupling protein 1 (UCP1). These findings indicate that ESE may represent a promising natural means of preventing obesity and obesity-related metabolic diseases.

Identification and Characterization of Carnitine Palmitoyltransferase 1 (cpt 1) Genes in Nile Tilapia, Oreochromis niloticus

Four cpt 1 genes ( cpt 1α1a, cpt 1α2a, cpt 1α2b, and cpt 1β) were identified in the Nile tilapia genome. Two transmembrane helix domains (TMH) were identified for Cpt 1α1a, Cpt 1α2a, and Cpt 1β, while Cpt 1α2b had only one TMH domain. Evidence was found of conserved gene synteny between cpt 1 genes from Nile tilapia and the cpt 1/CPT 1 genes of zebrafish and human. Phylogenetic analysis showed that Nile tilapia Cpt 1 sequences clustered in distinct clades with their orthologous Cpt 1/CPT 1 from other vertebrates. Nile tilapia cpt 1α1a, cpt 1α2a, cpt 1α2b, and cpt 1β contain 18 coding exons encoding polypeptides of 771, 784, 788, and 786 amino acids in length, respectively. The cpt 1 genes were determined in all the tested tissues with varying tissue distribution patterns. These findings suggest that (1) cpt 1α1a, cpt 1α2a, and cpt 1α2b arose in the Nile tilapia genome as a result of the teleost-specific whole-genome duplication; (2) nonfunctionalization is the most likely cause of the loss of cpt 1α1b in the Nile tilapia genome; (3) the different tissue-specific transcription of cpt 1α2a and cpt 1α2b may be either due to the sub- or the neo-functionalization of transcriptional control side.

Effects of Sargaquinoic Acid in Sargassum Serratifolium on Inducing Brown Adipocyte-like Phenotype in Mouse Adipocytes In Vitro

A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of Sargassum serratifolium (MES) stimulated adipose tissue browning and inhibited diet-induced obesity and metabolic syndrome. Sargaquinoic acid (SQA) is a major component in MES. We investigated the effects of SQA on the differentiation of preadipocytes to the beige adipocytes. SQA was treated in 3T3-L1 adipocytes differentiated under a special condition that has been reported to induce the browning of adipocytes. SQA at 10 µM reduced lipid accumulation by approximately 23%. SQA at 2.5 – 10 µM induced the differentiation of white adipocytes to beige adipocytes partially by increasing the mitochondrial density and the expression of beige/brown adipocyte markers. In addition, SQA activated lipid catabolic pathways, evidenced by the increased expression levels of perilipin, carnitine palmitoyltransferase 1, and acyl-CoA synthetase long-chain family member 1. As a partial mechanism, biochemical and in silico analyses indicate that SQA activated AMP-activated protein kinase signaling in adipocytes.