Branched-chain amino acid modulation of lipid metabolism, gluconeogenesis, and inflammation in a finishing pig model: targeting leucine and valine.

Branched-chain amino acids (BCAAs) play a regulatory role in adipogenesis and energy balance. Therefore, this study aimed to investigate the impact of BCAA supplements, especially leucine (Leu) and valine (Val) supplementation, on lipid metabolism and related disorders in a finishing pig model. The results demonstrated that Leu (1%) and Val decreased serum as well as hepatic lipid accumulation. Moreover, metabolomics and lipidomics analyses revealed that Leu and Val markedly downregulated the level of various lipid species in the liver. This outcome may be explained by Leu and Val promoting cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/hormone-sensitive triglyceride lipase (HSL) signaling pathways. Leu and Val altered the fatty acid composition in distinct adipose tissues and decreased the levels of inflammatory factors. Additionally, they significantly decreased back fat thickness, and the results of the fatty acid profiles demonstrated that Leu and Val significantly increased the levels of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) while decreasing those of saturated fatty acids (SFAs), especially in back fat and abdominal fat. Besides, Leu and Val restored glucose homeostasis by suppressing gluconeogenesis through the serine/threonine protein kinase (AKT)/transcription factor forkhead box O1 (FOXO1) signaling pathway in the liver and back fat. In summary, these results suggest that Leu and Val may serve as key regulators for modulating lipid metabolism and steatosis.

Clinical Value Analysis of Hepatectomy Based on Minimally Invasive Surgical Imaging for Hepatolithiasis.

Objective: To investigate the clinical value of hepatectomy based on minimally invasive surgical images in the treatment of hepatolithiasis. Methods: The clinical data of 87 patients with hepatolithiasis who received treatment in the Department of General Surgery of our hospital from February 2020 to September 2021 were retrospectively analyzed. According to different surgical methods, the patients were divided into minimally invasive group (n = 43) and laparotomy group (n = 44). Perioperative conditions and stone clearance rate were compared. Results: The preoperative conditions of patients in the two groups were comparable, and the average operation time in the minimally invasive group was significantly longer than that in the laparotomy group (t = 18.783,P < 0.001). There was no significant difference in intraoperative bleeding, postoperative fasting time, postoperative complications, and stone clearance between the two groups (P > 0.05). Postoperative hospital stay was significantly lower in the minimally invasive group than that in the laparotomy group (t = -0.486,P < 0.001). Conclusion: Hepatectomy based on minimally invasive surgical imaging for hepatolithiasis is safe and feasible, has high clinical value, and can achieve similar short-term clinical efficacy to laparotomy and reduce the postoperative hospital stay of patients, reflecting its minimally invasive advantages, and it is worthy of clinical application.

A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c-Myc Transcription Activity Inhibition in Liver Cancer.

Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/ß-catenin, TGF-ß, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.

Threonine supplementation prevents the development of fat deposition in mice fed a high-fat diet.

Obesity is the main factor involved in the onset of many diseases. Threonine supplementation has been demonstrated to reduce fat mass and serum triglycerides in already obese mice. However, it is unclear whether threonine could inhibit the development of obesity in mice without previous high-fat diet induction. In the present study, mice were fed a chow diet (CD) or a high-fat diet (HFD), supplemented or not with threonine (3.0% in drinking water) for 15 weeks. Results showed that mice subjected to chronic threonine supplementation showed decreased body weight, epididymal white adipose tissue weight, serum low-density lipoprotein cholesterol, and total cholesterol in comparison with HFD-fed mice. In the epididymal adipose tissue, gene expressions of sterol regulatory element-binding protein 1c and fatty acid synthase were up-regulated, while hormone sensitive lipase, adiponectin and fibroblast growth factor 21 were down-regulated. In the liver tissue, gene expressions of sirtuin1, adenosine monophosphate-activated protein kinase and peroxisome proliferator activated receptor γ co-activator 1α were up-regulated by threonine supplementation in HFD-fed mice. These results suggest that long-term threonine supplementation inhibited fat mass and improved lipid metabolism, making it a potential agent to prevent the development of diet-induced obesity.

Leucine, but not isoleucine or valine, affects serum lipid profiles and browning of WAT in mice.

Branched chain amino acids (BCAA), especially leucine (Leu), have been reported to decrease fat deposition. However, opposite effects of BCAA on lipid metabolism have been observed. To determine the role of BCAA in lipid metabolism, an amino acid-defined diet was formulated and C57BL/6J mice were assigned into the following groups: amino acid-defined control diet and control diet supplemented with Leu, isoleucine, or valine. Nitrogen was balanced by proportionally mixed amino acids except BCAA. Results showed that dietary Leu supplementation significantly increased the levels of serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and urea nitrogen. Metabolomics showed that biosynthesis of unsaturated fatty acids was altered by Leu supplementation. Leu treatment up-regulated the expression of genes related to fat synthesis and down-regulated the expression of genes related to fatty acid synthesis. Furthermore, the genes and proteins of selective markers involved in browning of white adipose tissue (WAT) were up-regulated by dietary supplementation with Leu. This study indicated that dietary supplementation with Leu, but not isoleucine or valine, significantly affected lipid metabolism by regulating lipid metabolism-related genes and serum fatty acid concentration, providing a new tool in the management of obesity and metabolic disorders.

Dietary supplementation with aromatic amino acids decreased triglycerides and alleviated hepatic steatosis by stimulating bile acid synthesis in mice.

Emerging evidence shows that amino acids can modulate lipid metabolism. Aromatic amino acids (AAAs) serve as important precursors of several neurotransmitters and metabolic regulators that play a vital role in regulating nutrient metabolism. But whether AAAs have a lipid-lowering function remains unknown. Here mice were fed amino acid-defined diets containing AAAs at 1.82% and 3.64% for 3 weeks. We demonstrated that double AAA intake significantly decreased the serum and hepatic triglycerides and serum low-density lipoprotein cholesterol, but increased the high-density lipoprotein cholesterol as well as insulin tolerance. Combined metabolomic and transcriptomic analysis showed that the hepatic acidic pathway of bile acid synthesis was responsible for the improvement in lipid metabolism by AAA treatment. This study suggests that AAAs have the potential to ameliorate steatosis and provides a new alternative to improve lipid metabolism.

Threonine, but Not Lysine and Methionine, Reduces Fat Accumulation by Regulating Lipid Metabolism in Obese Mice.

Some amino acids (AAs) have been proven to suppress fat mass and improve insulin sensitivity. However, the impact of important essential AAs, threonine, lysine, and methionine, on obesity has not been clarified. In the present study, after an 8 week period of obesity induction, mice were grouped to receive either a high-fat diet (HFD) or HFD supplemented with lysine, threonine, or methionine (3% in drinking water) for another 10 weeks. The results showed that dietary supplementation with threonine significantly decreased body weight, epididymal and perirenal fat pad weights, serum concentrations of glucose, triacylglycerols, total cholesterol, and LDL-cholesterol compared to the HFD group. HOMA-IR and serum leptin and adiponectin were improved by threonine supplementation. In epididymal adipose tissue, threonine treatment significantly down-regulated the expression levels of lipogenesis and up-regulated expressions of lipolysis compared to the HFD group. Threonine addition stimulated the expression of UCP-1 and related genes in brown adipose tissue. However, lysine or methionine supplementation showed little effect on body weight, WAT weight, serum lipid profiles, and lipid-metabolism-related gene expressions of HFD-fed mice. These findings suggest that threonine inhibited fat mass and improved lipid metabolism of already obese mice, providing a potential agent in treating obesity.