Lactucopicrin promotes fatty acid ß-oxidation and attenuates lipid accumulation through adenosine monophosphate-activated protein kinase activation in free fatty acid-induced human hepatoblastoma cancer cells.

With its annually increasing prevalence, non-alcoholic fatty liver disease (NAFLD) has become a serious threat to people's life and health. After a preliminary research, we found that Lactucopicrin has pharmacological effects, such as lowering blood lipids and protecting the liver. Further research showed its significant activation for fatty acid ß-oxidase hydroxyacyl-coenzyme A (CoA) dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), so we hypothesized that Lactucopicrin could ameliorate lipid accumulation in hepatocytes by promoting fatty acid ß-oxidation. In this study, free fatty acid (FFA)-induced human hepatoblastoma cancer cells (HepG2) were used to establish an in vitro NAFLD model to investigate the molecular basis of Lactucopicrin in regulating lipid metabolism. Staining with Oil red O and measurements of triglyceride (TG) content, fatty acid ß-oxidase (FaßO) activity, reactive oxygen species (ROS) content, mitochondrial membrane potential, and adenosine triphosphate (ATP) content were used to assess the extent to which Lactucopicrin ameliorates lipid accumulation and promotes fatty acid ß-oxidation. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot methods were used to explore the regulatory effects of Lactucopicrin on factors related to fatty acid ß-oxidation. Results showed that Lactucopicrin downregulated phosphorylated mammalian target of rapamycin (P-mTOR) by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway and upregulated the messenger RNA (mRNA) and protein expression levels of coactivators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)), transcription factors (peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ)), and oxidative factors (carnitine palmitoyltransferase 1A (CPT1A) and HADHA). This phenomenon resulted in a significant increase in FaßO activity, ATP content, and JC-1 and a significant decrease in ROS level, TG content, and intracellular lipid droplets. With the addition of Dorsomorphin, all the effects of Lactucopicrin intervention were suppressed. In summary, Lactucopicrin promotes fatty acid ß-oxidation by activating the AMPK pathway, thereby ameliorating FFA-induced intracellular lipid accumulation in HepG2 cells.

Gestational supplementation of Bifidobacterium, Lactobacillus, and Streptococcus thermophilus attenuates hepatic steatosis in offspring mice through promoting fatty acid ß-oxidation.

Currently, Bifidobacterium, Lactobacillus, and Streptococcus thermophilus (BLS) are widely recognized as the crucially beneficial bacteria in the gut. Many preclinical and clinical studies have shown their protective effects against non-alcoholic fatty liver disease (NAFLD). However, whether gestational BLS supplementation could alleviate NAFLD in the offspring is still unknown. Kunming mice were given a high-fat diet (HFD) for 4 weeks before mating. They received BLS supplementation by gavage during pregnancy. After weaning, offspring mice were fed with a regular diet up to 5 weeks old. Gestational BLS supplementation significantly increased the abundance of Actinobacteriota, Bifidobacterium, and Faecalibaculum in the gut of dams exposed to HFD. In offspring mice exposed to maternal HFD, maternal BLS intake significantly decreased the ratio of Firmicutes to Bacteroidetes as well as the relative abundance of Prevotella and Streptococcus, but increased the relative abundance of Parabacteroides. In offspring mice, maternal BLS supplementation significantly decreased the hepatic triglyceride content and mitigated hepatic steatosis. Furthermore, maternal BLS supplementation increased the glutathione content and reduced malondialdehyde content in the liver. In addition, mRNA and protein expression levels of key rate-limiting enzymes in mitochondrial ß-oxidation (CPT1α, PPARα, and PGC1α) in the livers of offspring mice were significantly increased after gestational BLS supplementation. Thus, gestational BLS supplementation may ameliorate maternal HFD-induced steatosis and oxidative stress in the livers of offspring mice by modulating fatty acid ß-oxidation.

Identification of pine wood nematode (Bursaphelenchus xylophilus) loading response genes in Japanese pine sawyer (Monochamus alternatus) through comparative genomics and transcriptomics.

BACKGROUND: Pine wood nematode (PWN; Bursaphelenchus xylophilus) is the causative agent of pine wilt disease (PWD), which is considered the most dangerous biohazard to conifer trees globally. The transmission of PWN relies on insect vectors, particularly the Japanese pine sawyer (JPS; Monochamus alternatus). However, the molecular mechanism underlying PWN-JPS assembly remains largely unknown. RESULTS: Here, we found that both geographical and gender could significantly affect the PCA (PWN carrying amount) of JPS; thus, JPS transcriptomes from diverse locations and genders were explored regard to PWN loading. Due to the shortage of genomes, we developed a full-length reference transcriptome for analyzing next-generation sequencing data. A comparative genomic study was performed, and 11 248 potential PWN-carrying associate genes (ß) were nominated in JPS by using the reported genomes of PWN and non-PWN carrier insect species. Then, 151 differentially expressed transcripts (DETs), 28 of them overlapped with ß, correlated with the PCA of JPS were nominated by RNA-Seq, and found that fatty acid ß-oxidation might be the key factor that affected the PCA of JPS. Furthermore, JPS fatty acid ß-oxidation rates were experimentally decreased using the inhibitor Etomoxir, leading to an increased PCA of JPS. Meanwhile, silencing MaCPT1 in JPS by RNA interference led to a decreased fatty acid ß-oxidation rate and increased PCA of JPS. CONCLUSIONS: In conclusion, MaCPT1 was able to decrease the PWN-JPS assembly formation through the fatty acid ß-oxidation of JPS. These results provide new insights for exploring the impact of PWN invasion on JPS. © 2024 Society of Chemical Industry.

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review).

Tumor occurrence and progression are closely associated with abnormal energy metabolism and energy metabolism associated with glucose, proteins and lipids. The reprogramming of energy metabolism is one of the hallmarks of cancer. As a form of energy metabolism, fatty acid metabolism includes fatty acid uptake, de novo synthesis and ß­oxidation. In recent years, the role of abnormal fatty acid ß­oxidation in tumors has gradually been recognized. Mitochondrial trifunctional protein (MTP) serves an important role in fatty acid ß­oxidation and HADH (two subtypes: α subunit, HADHA and ß subunit, HADHB) are important subunits of MTP. HADH participates in the steps of 2, 3 and 4 fatty acid ß­oxidation. However, there is no review summarizing the specific role of HADH in tumors. Therefore, the present study focused on HADH as the main indicator to explore the changes in fatty acid ß­oxidation in several types of tumors. The present review summarized the changes in HADH in 11 organs (cerebrum, oral cavity, esophagus, liver, pancreas, stomach, colorectum, lymph, lung, breast, kidney), the effect of up­ and downregulation and the relationship of HADH with prognosis. In summary, HADH can be either a suppressor or a promoter depending on where the tumor is located, which is closely associated with prognostic assessment. HADHA and HADHB have similar prognostic roles in known and comparable tumors.

AKAP1 Deficiency Attenuates Diet-Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes.

Altering the balance between energy intake and expenditure is a major strategy for treating obesity. Nonetheless, despite the progression in antiobesity drugs on appetite suppression, therapies aimed at increasing energy expenditure are limited. Here, knockout ofAKAP1, a signaling hub on outer mitochondrial membrane, renders mice resistant to diet-induced obesity.AKAP1 knockout significantly enhances energy expenditure and thermogenesis in brown adipose tissues (BATs) of obese mice. Restoring AKAP1 expression in BAT clearly reverses the beneficial antiobesity effect in AKAP1-/- mice. Mechanistically, AKAP1 remarkably decreases fatty acid ß-oxidation (FAO) by phosphorylating ACSL1 to inhibit its activity in a protein-kinase-A-dependent manner and thus inhibits thermogenesis in brown adipocytes. Importantly, AKAP1 peptide inhibitor effectively alleviates diet-induced obesity and insulin resistance. Altogether, the findings demonstrate that AKAP1 functions as a brake of FAO to promote diet-induced obesity, which may be used as a potential therapeutic target for obesity.

Vaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid ß-Oxidation.

Background Defects in the renal fatty acid ß-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qß virus-like particles group and the PCSK9Qß-003 vaccine group. Mice of the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine (100 µg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qß virus-like particles groups, the PCSK9Qß-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qß-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qß-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid ß-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qß-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid ß-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.