Excessive Lipid Accumulation Research Articles

The Role of Gut Microbiota-Bile Acids Axis in the Progression of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25–30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake. The increasing prevalence of NAFLD will lead to an increasing number of cirrhosis patients, as well as hepatocellular carcinoma (HCC) requiring liver transplantation, while the current treatments for NAFLD and its advanced diseases are suboptimal. Accordingly, it is necessary to find signaling pathways and targets related to the pathogenesis of NAFLD for the development of novel drugs. A large number of studies and reviews have described the critical roles of bile acids (BAs) and their receptors in the pathogenesis of NAFLD. The gut microbiota (GM), whose composition varies between healthy and NAFLD patients, promotes the transformation of more than 50 secondary bile acids and is involved in the pathophysiology of NAFLD through the GM-BAs axis. Correspondingly, BAs inhibit the overgrowth of GM and maintain a healthy gut through their antibacterial effects. Here we review the biosynthesis, enterohepatic circulation, and major receptors of BAs, as well as the relationship of GM, BAs, and the pathogenesis of NAFLD in different disease progression. This article also reviews several therapeutic approaches for the management and prevention of NAFLD targeting the GM-BAs axis.

Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens

Adipose tissue expansion involves both differentiation of new precursors and size increase of mature adipocytes. While the two processes are well balanced in healthy tissues, obesity and diabetes type II are associated with abnormally enlarged adipocytes and excess lipid accumulation. Previous studies suggested a link between cell stiffness, volume and stem cell differentiation, although in the context of preadipocytes, there have been contradictory results regarding stiffness changes with differentiation. Thus, we set out to quantitatively monitor adipocyte shape and size changes with differentiation and lipid accumulation. We quantified by optical diffraction tomography that differentiating preadipocytes increased their volumes drastically. Atomic force microscopy (AFM)-indentation and -microrheology revealed that during the early phase of differentiation, human preadipocytes became more compliant and more fluid-like, concomitant with ROCK-mediated F-actin remodelling. Adipocytes that had accumulated large lipid droplets were more compliant, and further promoting lipid accumulation led to an even more compliant phenotype. In line with that, high fat diet-induced obesity was associated with more compliant adipose tissue compared to lean animals, both for drosophila fat bodies and murine gonadal adipose tissue. In contrast, adipose tissue of diabetic mice became significantly stiffer as shown not only by AFM but also magnetic resonance elastography. Altogether, we dissect relative contributions of the cytoskeleton and lipid droplets to cell and tissue mechanical changes across different functional states, such as differentiation, nutritional state and disease. Our work therefore sets the basis for future explorations on how tissue mechanical changes influence the behaviour of mechanosensitive tissue-resident cells in metabolic disorders.

NAFLD: Mechanisms, Treatments, and Biomarkers.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.

Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy. Deleting N-linked glycosylation gene ALG3 in mouse cancer cells substantially attenuates their growth in mice in a manner depending on cytotoxic T cells. Furthermore, ALG3 inhibition or N-linked glycosylation inhibitor tunicamycin treatment synergizes with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer. Mechanistically, we found that inhibiting ALG3 induced deficiencies of post-translational N-linked glycosylation modification and led to excessive lipid accumulation through sterol-regulated element-binding protein (SREBP1)-dependent lipogenesis in cancer cells. N-linked glycosylation deficiency-mediated lipid hyperperoxidation induced immunogenic ferroptosis of cancer cells and promoted a pro-inflammatory microenvironment, which boosted anti-tumor immune responses. In human subjects with cancer, elevated levels of ALG3 expression in tumor tissues are associated with poor patient survival. Taken together, we reveal an unappreciated role of ALG3 in regulating tumor immunogenicity and propose a potential therapeutic strategy for enhancing cancer immunotherapy.

Inhibition of fat accumulation, lipid dysmetabolism, cardiac inflammation, and improved nitric oxide signalling mediate the protective effects of lycopene against cardio-metabolic disorder in obese female rats

Obesity, hallmarked by excessive lipid accumulation and dysregulation, continues to escalate the prevalence of cardiometabolic diseases, and is a foremost cause of deaths globally. Alternative therapeutic agents are urgently needed. This study hypothesized that lycopene could proffer beneficial effects against obesity-induced cardiometabolic changes. Obesity was induced using a Western-style diet. Female albino rats (n=36) were randomized into 6 groups of 6 rats each: normal control, obese control, obese+lycopene (20 mg/kg body weight [b.wt.]), obese+lycopene (40 mg/kg b.wt.), lycopene (20 mg/kg b.wt.), and lycopene (40 mg/kg b.wt.). The study was 10 weeks. Obese rats had significantly higher (P< .05) body weight and total body fat. Lipids (triacylglycerol, cholesterol [CHOL], and free fatty acids), cardiac injury markers (troponin-T, creatine kinase-myocardial band, and malondialdehyde), and cardiovascular risk markers (low-density lipoprotein-CHOL, atherogenic and coronary risk indices) were significantly (P< .05) elevated in obese rats compared with control groups. However, obesity significantly reduced high-density lipoprotein-CHOL and impaired cardiac nitric oxide signalling. Pro-inflammatory mediators (nuclear factor-κB-p65, interleukin-1β [IL-1β], and IL-6) transcripts were increased in the heart of obese rats, whereas cardiac IL-10 expression was repressed. Treatment with lycopene reduced lipid concentrations, normalized lipid and lipoprotein metabolism, augmented nitric oxide concentration and IL-10 messenger RNA transcripts, and attenuated the expression of pro-inflammatory mediators. These findings delineate the role of lycopene in the attenuation of cardiometabolic disorders potentiated by obesity.

Host hepatic metabolism is modulated by gut microbiota-derived sphingolipids

Microbially-derived gut metabolites are important contributors to host phenotypes, many of which may link microbiome composition to metabolic disease. However, relatively few metabolites with known bioactivity have been traced from specific microbes to host tissues. Here, we use a labeling strategy to characterize and trace bacterial sphingolipids from the gut symbiont Bacteroides thetaiotaomicron to mouse colons and livers. We find that bacterial sphingolipid synthesis rescues excess lipid accumulation in a mouse model of hepatic steatosis and observe the transit of a previously uncharacterized bacterial sphingolipid to the liver. The addition of this sphingolipid to hepatocytes improves respiration in response to fatty-acid overload, suggesting that sphingolipid transfer to the liver could potentially contribute to microbiota-mediated liver function. This work establishes a role for bacterial sphingolipids in modulating hepatic phenotypes and defines a workflow that permits the characterization of other microbial metabolites with undefined functions in host health.

Mechanisms of ductular reaction in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.

Mesencephalic astrocyte-derived neurotrophic factor alleviates non-alcoholic steatohepatitis induced by Western diet in mice.

Excessive lipid accumulation, inflammation, and fibrosis in the liver are the major characteristics of non-alcoholic steatohepatitis (NASH). Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays an important role in metabolic homeostasis, raising the possibility that it is involved in NASH. Here, we reduced and increased MANF levels in mice in order to explore its influence on hepatic triglyceride homeostasis, inflammation, and fibrosis during NASH progression. The MANF expression was decreased in Western diet-induced NASH mice. In vivo, liver-specific MANF knockout exacerbated hepatic lipid accumulation, inflammation, and fibrosis of mice induced by Western diet, while liver-specific MANF overexpression mitigated these NASH pathogenic features. In vitro, knocking down MANF in primary hepatocyte cultures aggravated hepatic steatosis and inflammation, which MANF overexpression markedly attenuated. Studies in vitro and in vivo suggested that MANF regulated hepatic lipid synthesis by modulating SREBP1 expression. Inhibiting SREBP1 in primary hepatocytes blocked lipid accumulation after MANF knockdown. MANF overexpression reversed LXRs agonist GW3965 induced SREBP1 and LIPIN1 expression. MANF decreased the expression of pro-inflammatory cytokines by inhibiting NF-κB phosphorylation. These results suggest that MANF can protect against NASH by regulating SREBP1 expression and NF-κB signaling.

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD).

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress-related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

Inhibition of autophagy impairs free fatty acid-induced excessive lipid accumulation in hepatocellular carcinoma and hepatic cells

Autophagy is a reparative life-sustaining process. Dysfunctions of autophagy play an important role in the progression of chronic liver diseases. The role of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is still controversial. This study aimed to analyse the roles and molecular mechanisms of autophagy in NAFLD. In hepatic L02 and liver cancer cells (HuH-7), nonalcoholic fatty liver (NAFL) cell model was induced by free fatty acids (FFA). The cytotoxic effect was measured by MTS assay. Lipid droplets were detected by immunofluorescence assay and flow cytometry. The autophagy-related genes were measured by Western blot analysis. The autophagy inhibitor 3-methyladenine (3-MA) was used to block the autophagy. FFA induced a significant increase in the intracellular content of lipid droplets, and the accumulation of fatty droplets was dose-dependent in L02 and HuH-7 cells. FFA (800 lM) had no cytotoxic effect on L02 and HuH-7 cells. The levels of LC3-II/LC3-I and BECN1 were increased, but the level of p62 was decreased in the NAFL cell models. The expression of these genes was dose-dependent in the NAFL cell models. Intracellular lipid accumulation was associated with the upregulation of LC3-II/LC3-I and BECN1 and the deregulation of p62 in the NAFL cell models. The autophagy inhibitor 3-MA suppressed the FFA-induced autophagy in the NAFL cell models. Furthermore, 3-MA treatment significantly alleviated the accumulation of lipid droplets in L02 and HuH-7 cells. Our results suggest that autophagy has a significant effect on lipid accumulation in the NAFL cell models. Inhibition of autophagy impairs FFA-induced excessive lipid accumulation in hepatocellular carcinoma and hepatic cells.

Pro-Inflammatory Profile of Adipokines in Obesity Contributes to Pathogenesis, Nutritional Disorders, and Cardiovascular Risk in Chronic Kidney Disease.

Obesity is a disease which leads to the development of many other disorders. Excessive accumulation of lipids in adipose tissue (AT) leads to metabolic changes, including hypertrophy of adipocytes, macrophage migration, changes in the composition of immune cells, and impaired secretion of adipokines. Adipokines are cytokines produced by AT and greatly influence human health. Obesity and the pro-inflammatory profile of adipokines lead to the development of chronic kidney disease (CKD) through different mechanisms. In obesity and adipokine profile, there are gender differences that characterize the male gender as more susceptible to metabolic disorders accompanying obesity, including impaired renal function. The relationship between impaired adipokine secretion and renal disease is two-sided. In the developed CKD, the concentration of adipokines in the serum is additionally disturbed due to their insufficient excretion by the excretory system caused by renal pathology. Increased levels of adipokines affect the nutritional status and cardiovascular risk (CVR) of patients with CKD. This article aims to systematize the current knowledge on the influence of obesity, AT, and adipokine secretion disorders on the pathogenesis of CKD and their influence on nutritional status and CVR in patients with CKD.

The Protective Effects of Ganoderic Acids from Ganoderma lucidum Fruiting Body on Alcoholic Liver Injury and Intestinal Microflora Disturbance in Mice with Excessive Alcohol Intake.

This study aimed to investigate the protective effects of ganoderic acids (GA) from Ganoderma lucidum against liver injury and intestinal microbial disorder in mice with excessive alcohol intake. Results showed GA supplement significantly inhibited the abnormal elevation of the liver index, serum lipid parameters, aspartate aminotransferase and alanine aminotransferase in mice exposed to alcohol intake, and also significantly protected the excessive lipid accumulation and pathological changes. Alcohol-induced oxidative stress in the liver was significantly ameliorated by GA intervention through reducing the levels of maleic dialdehyde and lactate dehydrogenase and increasing the levels of glutathione, catalase, superoxide dismutase and alcohol dehydrogenase. Intestinal microbiota profiling demonstrated GA intervention modulated the composition of intestinal microflora by increasing the levels of Lactobacillus, Faecalibaculum, Romboutsia, Bifidobacterium and decreasing the Helicobacter level. Furthermore, liver metabolomic profiling suggested GA intervention had a remarkable regulatory effect on liver metabolism with excessive alcohol consumption. Moreover, GA intervention regulated mRNA levels of alcohol metabolism, fatty lipid metabolism, oxidative stress, bile acid biosynthesis and metabolism-related genes in the liver. Conclusively, these findings demonstrate GA intervention can significantly relieve alcoholic liver injury and it is hopeful to become a new functional food ingredient for the prevention of alcoholic liver injury.

Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver.

Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.

Mutation of spexin2 promotes feeding, somatic growth, adiposity, and insulin resistance in zebrafish.

Spexin2 (spx2) is a newly identified gene in vertebrates, but its biological functions remain unclear. In this study, we cloned the full-length cDNA of spx2 in zebrafish. The 288-bp open reading frame encodes a protein of 95 amino acids that contains a 14 amino acids mature peptide. Spx2 is highly expressed in brain and testis. Its expression was significantly downregulated in the hypothalamus after feeding treatment and 7 days of food deprivation. Using a zebrafish spx2-/- mutant line, we observed a greater amount of food intake and changes in mRNA levels of feeding factors. We found that, SPX2 acts as a satiety factor that inhibits food intake by downregulating the expression of agouti-related neuropeptide (agrp). Moreover, spx2 mutant fish exhibited a larger body size, excessive lipid accumulation, and insulin resistance. Taken together, our results revealed that SPX2 functions as a satiety factor involved in energy metabolic regulation in zebrafish.

Effects of Keemun and Dianhong Black Tea in Alleviating Excess Lipid Accumulation in the Liver of Obese Mice: A Comparative Study.

The chemical compositions of black teas differ greatly and may have different health benefits; however, systematic investigations into such benefits are lacking. Here, the chemical profiles of Keemun black tea (KBT) and Dianhong black tea (DBT), two common categories of tea in China, were analyzed, and their lipid-lowering effects in male C57BL/6 mice fed a high-fat diet (60% energy from fat) or the diet supplemented with 2% black tea powder for 15 weeks were investigated. The compounds most crucial in differentiating KBT and DBT were determined to be phenolic compounds, theanine, and D-psicose. DBT was more effective than KBT in preventing excess hepatic fat accumulation. Both black teas effectively and comparably altered the mRNA levels of hepatic lipid–metabolizing genes. DBT had more favorable effects in stimulating fecal fat excretion than did KBT. The differentiating compounds with the higher values of variable importance in the projection (VIP) might predominantly contribute to the different health benefits; however, the most essential compound or combination of compounds requires clarification.

Taurine Ameliorates Tunicamycin-Induced Liver Injury by Disrupting the Vicious Cycle between Oxidative Stress and Endoplasmic Reticulum Stress.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver dysfunction characterized by excess lipid accumulation; non-alcoholic steatohepatitis can transform into more severe conditions, such as cirrhosis and hepatocellular carcinoma. Although several pharmacologic approaches have been evaluated in clinical trials, there are no approved therapies for NAFLD. Previous studies have suggested that taurine supplementation alleviates fatty liver; however, the underlying mechanism remains obscure. In this study, we investigated the beneficial effects of taurine on fatty liver injury in vivo induced by tunicamycin, a chemical endoplasmic reticulum (ER) stressor. The mice were administered 2% taurine for 2 weeks prior to intraperitoneal tunicamycin injection; after 72 h of treatment, the mice were euthanized. Tunicamycin treatment significantly increased the levels of serum ALT and AST and hepatic triglycerides. Notably, these changes were alleviated by taurine supplementation. Taurine normalized the protein and/or mRNA levels involved in ER stress signaling (IRE1a, p-IRE1a, ATF6, XBP1, BiP, and CHOP) and lipid metabolism (CD36, MTTP, and ApoB), which were dysregulated by tunicamycin treatment. The stimulation of hepatic lipid export by taurine was evidenced by the recovery of blood VLDL levels. Furthermore, taurine supplementation prevented tunicamycin-induced lipid peroxidation and decreased glutathione (GSH) levels by correcting abnormal cysteine catabolism involved in the production of both taurine and GSH. Therefore, taurine supplementation can prevent tunicamycin-induced liver injury by counteracting oxidative and ER stress.

4-Octyl Itaconate Prevents Free Fatty Acid-Induced Lipid Metabolism Disorder through Activating Nrf2-AMPK Signaling Pathway in Hepatocytes.

Nonalcoholic fatty liver disease (NAFLD), characterized with oxidative stress and hepatic steatosis, is a serious threat to human health. As a specific activator of nuclear factor E2-related factor 2 (Nrf2), the 4-octyl itaconate (4-OI) has the beneficial effects in antioxidant and anti-inflammation; however, whether 4-OI can alleviate hepatic steatosis and its mechanism is still unknown. The present study was aimed at investigating the protective effects of 4-OI on free fat acid- (FFA-) induced lipid metabolism disorder and its potential molecular mechanism in hepatocytes. The results showed that 4-OI treatment markedly alleviated FFA-induced oxidative stress and excessive lipid accumulation in hepatocytes. Mechanistically, 4-OI significantly suppressed the overproduction of reactive oxygen species (ROS) through activation of Nrf2; the downregulation of ROS level induced a downregulation of AMP-dependent protein kinase (AMPK) phosphorylation level which finally ameliorated excessive lipid accumulation in FFA-stimulated hepatocytes. In general, our data demonstrated that 4-OI relieves the oxidative stress and lipid metabolism disorder in FFA-stimulated hepatocytes; and these beneficial effects were achieved by activating the Nrf2-AMPK signaling pathway. These data not only expand the new biological function of 4-OI but also provide a theoretical basis for 4-OI to protect against lipid metabolism disorders and related diseases, such as NAFLD.

Platelets in Non-alcoholic Fatty Liver Disease.

Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.

Identifying Key Genes and Functionally Enriched Pathways of Diverse Adipose Tissue Types in Cattle.

Background: Fat is a tissue that not just stores energy and plays a protective role; it is also a vital endocrine organ that generates and integrates signals to influence metabolism. Meanwhile, the excessive accumulation of lipids in adipose tissue can lead to metabolic disturbance and diseases. To date, the complicated molecular mechanisms of bovine adipose tissue are still unknown. This study aimed to identify key genes and functionally enriched pathways in various adipose tissue types. Results: The RNAseq data of 264 samples were downloaded from Gene Expression Omnibus (GEO) and analyzed by weighted gene co-expression network analysis (WGCNA). We identified 19 modules that significantly associated with at least one adipose tissue type. The brown module from GSE39618 was most closely associated with intramuscular fat tissue, which contained 550 genes. These genes were significantly enriched in pathways that related to inflammation and disease, such as TNF signaling pathway, IL-17 signaling pathway, and NF-kappa B signaling pathway. The pink module (GSE39618) that contained 58 genes was most closely associated with omental fat tissue. The turquoise (GSE39618), blue (GSE116775), and yellow (GSE65125) module were most closely associated with subcutaneous fat tissue. Genes in these modules were significantly enriched in pathways related to fat metabolism, such as the PPAR signaling pathway, fatty acid metabolism and PI3K-Akt signaling pathway. At last, key genes for intramuscular fat (PTGS2 and IL6), omental fat (ARHGEF5 and WT1), and subcutaneous fat (KIT, QR6Q1, PKD2L1, etc.) were obtained and verified. In addition, it was found that IL10 and VCAM1 might be potential genes to distinguish adipose and muscle. Conclusion: The study applied WGCNA to generate a landscape of adipose tissue and provide a basis for identifying potential pathways and hub genes of different adipose tissue types.

Inhibitory Effect of Water Soluble Fraction of Monascus-Fermented Rice on Lipid Accumulation in 3T3 L1 Adipocyte

Excessive lipid accumulation in the body causes people to become overweight and obese, conditions that are associated with an amplified risk of serious diseases. The fungi of genus Monascus produce various secondary metabolites such as monacolins, citrinin and fungal pigments, which are water-insoluble and have inhibitory potency for the lipid accumulation in adipocytes. However, water-soluble adipogenesis inhibitors derived from Monascus-fermented products have not yet been reported. In this study, we investigated the inhibitory activity against intracellular lipid accumulation of water-soluble fractions of Monascus-fermented red mold rice (RMR) and red mold barley (RMB) on murine 3T3-L1 cells. Water soluble fractions of ten different Monascus strains were used and the inhibitory activity of their water-soluble fractions on lipid accumulation by differentiated 3T3-L1 cells was evaluated for 8 days using oil red staining. The water-soluble fraction from Monascus pilosus NBRC4507 fermented RMR cultivated at 30C for 14 days was selected since it showed comparatively the lowest relative lipid accumulation (62±1.2%), which indicated the highest inhibitory activity of lipid accumulation in adipocytes. To study the presence of monacolin and citrinin in the water soluble fractions, thin-layer chromatography was done and the results showed that the water-soluble fractions tested were free from both monacolin and citrinin. Therefore, the present study strongly suggested that the water-soluble components, except for monacolin and citrinin, in the water soluble fraction obtained from Monascus pilosus NBRC4507-fermented rice can be used as functional food material to control overweight and obesity.