In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis-a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.
Humans ; Mice ; Animals ; Non-alcoholic Fatty Liver Disease/metabolism* ; NF-kappa B/metabolism* ; Organelle Biogenesis ; Retrospective Studies ; Mice, Inbred C57BL ; Obesity/metabolism* ; Liver ; Inflammation/metabolism* ; Body Weight ; Lipid Metabolism ; Lipids ; Diet, High-Fat/adverse effects*

With the development of high-throughput sequencing technology, circular RNAs (circRNAs) have gradually become a hotspot in the research on non-coding RNA. CircRNAs are produced by the covalent circularization of a downstream 3' splice donor and an upstream 5' splice acceptor through backsplicing, and they are pervasive in eukaryotic cells. CircRNAs used to be considered byproducts of false splicing, whereas an explosion of related studies in recent years has disproved this misconception. Compared with the rich studies of circRNAs in animals, the study of circRNAs in plants is still in its infancy. In this review, we introduced the discovery of plant circRNAs, the discovery of plant circRNAs, the circularization feature, expression specificity, conservation, and stability of plant circRNAs and expounded the identification tools, main types, and biogenesis mechanisms of circRNAs. Furthermore, we summarized the potential roles of plant circRNAs as microRNA (miRNA) sponges and translation templates and in response to biotic/abiotic stress, and briefed the degradation and localization of plant circRNAs. Finally, we discussed the challenges and proposed the future directions in the research on plant circRNAs.
Animals ; MicroRNAs/metabolism* ; Organelle Biogenesis ; Plants/metabolism* ; Protein Biosynthesis/physiology* ; RNA, Circular/metabolism* ; RNA, Plant/metabolism* ; Research/trends* ; Stress, Physiological/genetics*

OBJECTIVE: To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides (LBP) in a non-alcoholic fatty liver disease (NAFLD) cell model. METHODS: Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids (FFA) mixture for 24 h to induce NAFLD cell model. Cells were divided into 5 groups, including control, model, low-, medium- and high dose LBP (30,100 and 300 µg/mL) groups. The monosaccharide components of LBP were analyzed with high performance liquid chromatography. Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining, respectively. Triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), adenosine triphosphate (ATP) and oxidative stress indicators were evaluated. Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot, respectively. RESULTS: Heteropolysaccharides with mannose and glucose are the main components of LBP. LBP treatment significantly decreased intracellular lipid accumulation as well as TG, ALT, AST and malondialdehyde levels (P<0.05 or P<0.01), increased the levels of superoxide dismutase, phospholipid hydroperoxide glutathione peroxidase, catalase, and ATP in NAFLD cell model (P<0.05). Meanwhile, the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated (P<0.05). CONCLUSION LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model.
Humans ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Lycium/metabolism* ; Catalase/metabolism* ; Organelle Biogenesis ; Alanine Transaminase ; Uncoupling Protein 2 ; Fatty Acids, Nonesterified ; Mannose ; Nuclear Respiratory Factor 1/metabolism* ; PPAR gamma/metabolism* ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Drugs, Chinese Herbal/pharmacology* ; Malondialdehyde/metabolism* ; Superoxide Dismutase/metabolism* ; Polysaccharides/pharmacology* ; Triglycerides ; RNA, Messenger ; Aspartate Aminotransferases ; Glucose ; Adenosine Triphosphate

BACKGROUND/OBJECTIVES: The NAD+ precursor nicotinamide riboside (NR) is a type of vitamin B3 found in cow's milk and yeast-containing food products such as beer. Recent studies suggested that NR prevents hearing loss, high-fat diet-induced obesity, Alzheimer's disease, and mitochondrial myopathy. The objective of this study was to investigate the effects of NR on inflammation and mitochondrial biogenesis in AML12 mouse hepatocytes. MATERIALS/METHODS: A subset of hepatocytes was treated with palmitic acid (PA; 250 µM) for 48 h to induce hepatocyte steatosis. The hepatocytes were treated with NR (10 µM and 10 mM) for 24 h with and without PA. The cell viability and the levels of sirtuins, inflammatory markers, and mitochondrial markers were analyzed. RESULTS: Cytotoxicity of NR was examined by PrestoBlue assay. Exposure to NR had no effect on cell viability or morphology. Gene expression of sirtuin 1 (Sirt1) and Sirt3 was significantly upregulated by NR in PA-treated hepatocytes. However, Sirt1 activities were increased in hepatocytes treated with low-dose NR. Hepatic pro-inflammatory markers including tumor necrosis factor-alpha and interleukin-6 were decreased in NR-treated cells. NR upregulated anti-inflammatory molecule adiponectin, and, tended to down-regulate hepatokine fetuin-A in PA-treated hepatocytes, suggesting its inverse regulation on these cytokines. NR increased levels of mitochondrial markers including peroxisome proliferator-activated receptor γ coactivator-1α, carnitine palmitoyltransferase 1, uncoupling protein 2, transcription factor A, mitochondrial and mitochondrial DNA in PA-treated hepatocytes. CONCLUSIONS: These data demonstrated that NR attenuated hepatic inflammation and increased levels of mitochondrial markers in hepatocytes.
Adiponectin ; alpha-2-HS-Glycoprotein ; Alzheimer Disease ; Animals ; Beer ; Carnitine O-Palmitoyltransferase ; Cell Survival ; Cytokines ; DNA, Mitochondrial ; Fatty Liver ; Gene Expression ; Hearing Loss ; Hepatocytes ; Inflammation ; Interleukin-6 ; Mice ; Milk ; Mitochondria ; Mitochondrial Myopathies ; Niacin ; Niacinamide ; Obesity ; Organelle Biogenesis ; Palmitic Acid ; Peroxisomes ; Sirtuin 1 ; Sirtuins ; Transcription Factors ; Tumor Necrosis Factor-alpha

BACKGROUND/OBJECTIVES: The study was conducted to evaluate the effects of dietary leucine supplementation on mitochondrial biogenesis and energy metabolism in the liver of normal birth weight (NBW) and intrauterine growth-retarded (IUGR) weanling piglets. MATERIALS/METHODS: A total of sixteen pairs of NBW and IUGR piglets from sixteen sows were selected according to their birth weight. At postnatal day 14, all piglets were weaned and fed either a control diet or a leucine-supplemented diet for 21 d. Thereafter, a 2 × 2 factorial experimental design was used. Each treatment consisted of eight replications with one piglet per replication. RESULTS: Compared with NBW piglets, IUGR piglets had a decreased (P < 0.05) hepatic adenosine triphosphate (ATP) content. Also, IUGR piglets exhibited reductions (P < 0.05) in the activities of hepatic mitochondrial pyruvate dehydrogenase (PDH), citrate synthase (CS), α-ketoglutarate dehydrogenase (α-KGDH), malate dehydrogenase (MDH), and complexes I and V, along with decreases (P < 0.05) in the concentration of mitochondrial DNA (mtDNA) and the protein expression of hepatic peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). Dietary leucine supplementation increased (P < 0.05) the content of ATP, and the activities of CS, α-KGDH, MDH, and complex V in the liver of piglets. Furthermore, compared to those fed a control diet, piglets given a leucine-supplemented diet exhibited increases (P < 0.05) in the mtDNA content and in the mRNA expressions of sirtuin 1, PGC-1α, nuclear respiratory factor 1, mitochondrial transcription factor A, and ATP synthase, H+ transporting, mitochondrial F1 complex, β polypeptide in liver. CONCLUSIONS: Dietary leucine supplementation may exert beneficial effects on mitochondrial biogenesis and energy metabolism in NBW and IUGR weanling piglets.
Adenosine Triphosphate ; Birth Weight* ; Citrate (si)-Synthase ; Diet ; DNA, Mitochondrial ; Energy Metabolism* ; Fetal Growth Retardation ; Leucine* ; Liver ; Malate Dehydrogenase ; Nuclear Respiratory Factor 1 ; Organelle Biogenesis* ; Oxidoreductases ; Parturition* ; Peroxisomes ; Pyruvic Acid ; Research Design ; RNA, Messenger ; Sirtuin 1 ; Transcription Factors

The aim of this study is to investigate the effects of intermittent ladder-climbing exercise training on mitochondrial biogenesis and ER stress of the cardiac muscle in high fat diet-induced obese middle-aged rats. We induced obesity over 6 weeks of period in 40 male Sprague-Dawley rats around 50 weeks old, and were randomly divided into four experimental groups: chow, HFD, exercise+HFD, and exercise+chow. The exercising groups underwent high-intensity intermittent training using a ladder-climbing and weight exercise 3 days/week for a total of 8 weeks. High-fat diet and concurrent exercise resulted in no significant reduction in body weight but caused a significant reduction in visceral fat weight (p<0.05). Expression of PPARδ increased in the exercise groups and was significantly increased in the high-fat diet+exercise group (p<0.05). Among the ER stress-related proteins, the expression levels of p-PERK and CHOP, related to cardiac muscle damage, were significantly higher in the cardiac muscle of the high-fat diet group (p<0.05), and were significantly reduced by intermittent ladder-climbing exercise training (p<0.05). Specifically, this reduction was greater when the rats underwent exercise after switching back to the chow diet with a reduced caloric intake. Collectively, these results suggest that the combination of intermittent ladder-climbing exercise training and a reduced caloric intake can decrease the levels of ER stress-related proteins that contribute to cardiac muscle damage in obesity and aging. However, additional validation is required to understand the effects of these changes on mitochondrial biogenesis during exercise.
Aging ; Animals ; Body Weight ; Diet ; Diet, High-Fat ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Energy Intake ; Humans ; Intra-Abdominal Fat ; Male ; Myocardium* ; Obesity ; Organelle Biogenesis* ; Rats* ; Rats, Sprague-Dawley

Obesity is known to induce inhibition of glucose uptake, reduction of lipid metabolism, and progressive loss of skeletal muscle function, which are all associated with mitochondrial dysfunction in skeletal muscle. Mitochondria are dynamic organelles that regulate cellular metabolism and bioenergetics, including ATP production via oxidative phosphorylation. Due to these critical roles of mitochondria, mitochondrial dysfunction results in various diseases such as obesity and type 2 diabetes. Obesity is associated with impairment of mitochondrial function (e.g., decrease in O₂ respiration and increase in oxidative stress) in skeletal muscle. The balance between mitochondrial fusion and fission is critical to maintain mitochondrial homeostasis in skeletal muscle. Obesity impairs mitochondrial dynamics, leading to an unbalance between fusion and fission by favorably shifting fission or reducing fusion proteins. Mitophagy is the catabolic process of damaged or unnecessary mitochondria. Obesity reduces mitochondrial biogenesis in skeletal muscle and increases accumulation of dysfunctional cellular organelles, suggesting that mitophagy does not work properly in obesity. Mitochondrial dysfunction and oxidative stress are reported to trigger apoptosis, and mitochondrial apoptosis is induced by obesity in skeletal muscle. It is well known that exercise is the most effective intervention to protect against obesity. Although the cellular and molecular mechanisms by which exercise protects against obesity-induced mitochondrial dysfunction in skeletal muscle are not clearly elucidated, exercise training attenuates mitochondrial dysfunction, allows mitochondria to maintain the balance between mitochondrial dynamics and mitophagy, and reduces apoptotic signaling in obese skeletal muscle.
Adenosine Triphosphate ; Apoptosis ; Energy Metabolism ; Glucose ; Homeostasis ; Lipid Metabolism ; Metabolism ; Mitochondria ; Mitochondrial Degradation ; Mitochondrial Dynamics ; Muscle, Skeletal* ; Obesity ; Organelle Biogenesis ; Organelles ; Oxidative Phosphorylation ; Oxidative Stress ; Respiration

Brown adipose generates heat via oxidation of fatty acids by a mitochondrial uncoupling protein 1 (UCP1)-dependent process. In addition, a subpopulation of cells within subcutaneous white adipose tissue, known as beige adipocytes, also plays a role in thermogenesis. The biogenesis of beige adipocytes is induced by thermogenic signals, such as chronic cold exposure. Recently, it has been reported that eosinophils, type 2 cytokines of IL-4/13, and alternatively activated macrophages control the thermogenic cycle of beige adipocytes. Alternatively, activated macrophages induce UCP1+ beige adipocytes through secretion of catecholamines. These results define the role of type 2 immune responses in the regulation of energy homeostasis.
Adipocytes ; Adipose Tissue, Brown ; Adipose Tissue, White ; Organelle Biogenesis* ; Catecholamines ; Cytokines ; Eosinophils* ; Fatty Acids ; Homeostasis ; Hot Temperature ; Macrophages* ; Thermogenesis

BACKGROUND: Panax ginseng has glucose-lowering effects, some of which are associated with the improvement in insulin resistance in skeletal muscle. Because mitochondria play a pivotal role in the insulin resistance of skeletal muscle, we investigated the effects of the ginsenoside Rg3, one of the active components of P. ginseng, on mitochondrial function and biogenesis in C2C12 myotubes. METHODS: C2C12 myotubes were treated with Rg3 for 24 hours. Insulin signaling pathway proteins were examined by Western blot. Cellular adenosine triphosphate (ATP) levels and the oxygen consumption rate were measured. The protein or mRNA levels of mitochondrial complexes were evaluated by Western blot and quantitative reverse transcription polymerase chain reaction analysis. RESULTS: Rg3 treatment to C2C12 cells activated the insulin signaling pathway proteins, insulin receptor substrate-1 and Akt. Rg3 increased ATP production and the oxygen consumption rate, suggesting improved mitochondrial function. Rg3 increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor, which are transcription factors related to mitochondrial biogenesis. Subsequent increased expression of mitochondrial complex IV and V was also observed. CONCLUSION: Our results suggest that Rg3 improves mitochondrial function and the expression of key genes involved in mitochondrial biogenesis, leading to an improvement in insulin resistance in skeletal muscle. Rg3 may have the potential to be developed as an anti-hyperglycemic agent.
Adenosine Triphosphate ; Blotting, Western ; Insulin ; Insulin Receptor Substrate Proteins ; Insulin Resistance ; Mitochondria ; Muscle Fibers, Skeletal* ; Muscle, Skeletal ; Nuclear Respiratory Factor 1 ; Organelle Biogenesis* ; Oxygen Consumption ; Panax ; Peroxisomes ; Polymerase Chain Reaction ; Reverse Transcription ; RNA, Messenger ; Transcription Factors

Endurance exercise training such as marathon can increase the ability of exercise performance. Muscle glycogen is associated with an exercise performance, because glycogen depletion is primary causes of muscle fatigue. This review summarizes the glycogen saving effect according to duration of endurance exercise training. Long-term endurance exercise-induced mitochondrial biogenesis contributes to glycogen saving effect that is reduced glycogen breakdown and lactate accumulation. Glycogen sparing is due to a smaller decrease in adenosine triphosphate and phosphocreatine and a smaller increase in inorganic phosphate in the working muscles. It takes required endurance exercise training for about 4 weeks or more. Single bout or short-term endurance exercise is not sufficient to bring an increase in functional mitochondria. But peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) increases rapidly after single bout of endurance exercise. PGC-1α downregulates glycogenolytic and glycolytic enzymes to reduce muscle glycogen breakdown and lactic acid accumulation after short-term endurance exercise.
Adenosine Triphosphate ; Glycogen* ; Glycogenolysis ; Lactic Acid ; Mitochondria ; Muscle Fatigue ; Muscle, Skeletal* ; Muscles ; Organelle Biogenesis ; Peroxisomes ; Phosphocreatine