Excessive Lipid Accumulation Research Articles

Role of MCPIP1 protein in lipid metabolism, liver homeostasis and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of lipids in hepatocytes. Among NAFLD patients, in 25% of them this disease progress to nonalcoholic steatohepatitis, which is characterized additionally by the development of inflammation and fibrosis of liver. Currently, it is estimated that 24% of the world’s population suffers from NAFLD. MCPIP1 protein is an RNase described as a negative regulator of inflammation. Also, MCPIP1 plays a role in lipid metabolism because it inhibits the process of adipogenesis and mice with a deletion of Zc3h12a gene are characterized by dyslipidemia and reduced body fat content. In the case of ischemia-reperfusion injury in liver, MCPIP1 is protective against the inflammation and damage of this organ. Lipid accumulation by hepatocytes is associated with a decrease of Mcpip1 level. In addition, MCPIP1 may influence the PPARγ-mediated lipogenesis process. Presence of Mcpip1 in both myeloid leukocytes and liver epithelial cells is crucial for the maintenance of liver homeostasis.

Glycerol monolaurate and triglycerol monolaurate alleviated high-fat diet induced lipid accumulation and damage of liver in zebrafish (Danio rerio)

The widespread use of high-fat diet (HFD) has significantly impacted cultured fish health. In this study, zebrafish were used as a model to explore the role of glycerol monolaurate (GML) and triglycerol monolaurate (TGML) in relieving excessive lipid accumulation and damage of liver caused by HFD and to reveal its possible mechanism. Zebrafish were fed with four kinds of experimental diets, including regular diet, HFD, and HFD supplemented with 1.5 g/kg GML and 1.5 g/kg TGML for 4 weeks. Serum biochemistry, histomorphology, expression of genes or proteins involved in lipid metabolism, inflammation and antioxidant stress of zebrafish were determined. Results showed that GML and TGML reduced the lipid synthesis, improved the lipid decomposition of liver, and consequently alleviated the lipid accumulation in the liver of zebrafish caused by the HFD. Further, GML and TGML improved antioxidant capacity of the liver, induced the genes expression of anti-inflammatory factors, and reduced the genes expression of pro-inflammatory factors, thereby alleviating liver oxidative stress and inflammation caused by HFD. Particularly, GML and TGML significantly enhanced the expression of AMPK which were inhibited by HFD. In summary, GML and TGML reduced the excessive lipid accumulation and damage in the liver of zebrafish caused by HFD, which may be by regulating AMPK.

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

Nonalcoholic fatty liver disease (NAFLD) includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis. We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver. The effect of combined lipid-lowering drugs (statins and anti-PCSK9 monoclonal antibody) were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators, such as alarmins, responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress. Proteomic analysis revealed a number of proteins whose abundance was altered. They were components of metabolic pathways including fatty-acid degradation, glycolysis/gluconeogenesis, and nonalcoholic fatty liver disease. Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH: ubiquinone oxidoreductase. The expression of a majority of cytochromes (P4502E1, b5, and c) were up-regulated by lipid-lowering treatment. Long-term hyperlipidemic stress, even with a low-fat diet and lipid-lowering treatment, was accompanied by alarmin release (annexins, galectins, HSPs, HMGB1, S100 proteins, calreticulin, and fibronectin) that generated local inflammation and induced liver steatosis and aggressive fibrosis (by high abundance of galectin 3, fibronectin, and calreticulin). The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent, combined lipid-lowering treatment with statin and inhibitor of PCSK9.

Adtrp regulates thermogenic activity of adipose tissue via mediating the secretion of S100b.

Brown and beige adipose tissues dissipate chemical energy in the form of heat to maintain your body temperature in cold conditions. The impaired function of these tissues results in various metabolic diseases in humans and mice. By bioinformatical analyses, we identified a functional thermogenic regulator of adipose tissue, Androgen-dependent tissue factor pathway inhibitor [TFPI]-regulating protein (Adtrp), which was significantly overexpressed in and functionally activated the mature brown/beige adipocytes. Hereby, we knocked out Adtrp in mice which led to multiple abnormalities in thermogenesis, metabolism, and maturation of brown/beige adipocytes causing excess lipid accumulation in brown adipose tissue (BAT) and cold intolerance. The capability of thermogenesis in brown/beige adipose tissues could be recovered in Adtrp KO mice upon direct β3-adrenergic receptor (β3-AR) stimulation by CL316,243 treatment. Our mechanistic studies revealed that Adtrp by binding to S100 calcium-binding protein b (S100b) indirectly mediated the secretion of S100b, which in turn promoted the β3-AR mediated thermogenesis via sympathetic innervation. These results may provide a novel insight into Adtrp in metabolism via regulating the differentiation and thermogenesis of adipose tissues in mice.

Overexpression of circ PTK2 suppresses the progression of nonalcoholic fatty liver disease via the miR-200c/SIK2/PI3K/Akt axis.

Excessive hepatic lipid accumulation is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A previous study showed that the circular RNA (circRNA) PTK2 was significantly downregulated in NAFLD mice. However, the detailed function of circ PTK2 in NAFLD remains unclear. A high-fat diet (HFD) was used to establish a mouse model of NAFLD, and free fatty acid (FFA) treatment was used to establish an in vitro model of NAFLD. Oil red O staining was used to evaluate lipid accumulation. The pathological changes in mice were observed by HE staining. Western blotting and RT-qPCR were applied to assess protein and mRNA levels, respectively. A dual luciferase reporter assay and RIP were used to explore the relationship among circ PTK2, miR-200c and SIK2. Circ PTK2 and SIK2 were downregulated and miR-200c was upregulated in NAFLD. Upregulation of circ PTK2 reversed lipid accumulation in FFA-treated HepG2 cells. Moreover, circ PTK2 bound to miR-200c, and SIK2 was identified as the direct target of miR-200c. Moreover, the miR-200c inhibitor-induced decrease in lipid accumulation was reversed by SIK2 knockdown. Furthermore, the impact of circ PTK2 overexpression on PI3K/Akt signaling was partially reversed by SIK2 silencing. Circ PTK2 overexpression alleviates NAFLD development via the miR-200c/SIK2/PI3K/Akt axis. Thus, our work might provide new methods for NAFLD treatment.

Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD.

The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reactive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy, oxidative phosphorylation, and mitochondrial biogenesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone receptor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD. Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell transcriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.

Platelet-Activating Factor Promotes the Development of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.

A Greater Improvement of Intrahepatic Fat Contents after 6 Months of Lifestyle Intervention Is Related to a Better Oxidative Stress and Inflammatory Status in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by the excessive accumulation of lipids in the liver parenchyma. To date, there is no effective pharmacological treatment against NAFLD. Objective: To assess the relationship between the improvement of the intrahepatic fat content (IFC) in patients with NAFLD and metabolic syndrome and biomarkers of oxidative stress and inflammation after 6 months of lifestyle intervention. Patients diagnosed with NAFLD (n = 60 adults; 40–60 years old) residing in the Balearic Islands, Spain, were distributed in tertiles attending the improvement of IFC calculated by magnetic resonance imaging (MRI). Anthropometrics, blood pressure, maximal oxygen uptake, and pro/antioxidant and inflammatory biomarkers were determined in plasma before and after the lifestyle intervention. The improvement in IFC levels was higher in tertile 3 with respect to tertiles 2 and 1. The greatest improvement in IFC is related to cardiorespiratory fitness and adherence to the Mediterranean diet (ADM). Higher reductions in weight, body mass index (BMI), and alanine aminotransferase (ALT) were observed in tertile 3 with respect to tertile 1 after 6 months of intervention. The improvement in catalase, irisin, and cytokeratin 18 plasma levels were higher in tertile 3, whereas no differences were observed in superoxide dismutase activity. Malondialdehyde and protein carbonyl levels, as biomarkers of oxidative damage, remained unchanged in all groups. The present data show that the reduction of IFC is associated with an improvement in pro/antioxidant and pro-inflammatory status and a better cardiorespiratory fitness in NAFLD patients.

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.