Pathogenesis Of Hepatic Steatosis Research Articles

FoxO6-Mediated TXNIP Induces Lipid Accumulation in the Liver through NLRP3 Inflammasome Activation.

Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown. This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6-null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism. We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1β through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells. The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver.

Bisphenol A induced hepatic steatosis by disturbing bile acid metabolism and FXR/TGR5 signaling pathways via remodeling the gut microbiota in CD-1 mice

Dysregulation of gut microbiota-mediated bile acid (BA) metabolism plays an important role in the pathogenesis of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Our previous studies found that bisphenol A (BPA) exposure induced hepatic steatosis and gut microbiota dysbiosis. However, whether the gut microbiota-dependent BA metabolism alterations were involved in BPA-induced hepatic steatosis remains unclear. Therefore, we explored the gut microbiota-related metabolic mechanisms of hepatic steatosis induced by BPA. Male CD-1 mice were exposed to low-dose BPA (50 μg/kg/day) for 6 months. Fecal microbiota transplantation (FMT) and broad-spectrum antibiotic cocktail (ABX) treatment were further adopted to test the role of gut microbiota in the adverse effects of BPA. We found that BPA induced hepatic steatosis in mice. Additionally, 16S rRNA gene sequencing showed that BPA reduced the relative abundance of Bacteroides, Parabacteroides and Akkermansia, which are associated with BA metabolism. Metabolomic analyses demonstrated that BPA significantly altered the ratio of conjugated to unconjugated BAs and increased the total level of taurine-α/β-muricholic acid while decreasing the level of chenodeoxycholic acid, thus inhibiting the activation of special receptors, including farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), in the ileum and liver. The inhibition of FXR reduced short heterodimer partner and subsequently induced cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, which is related to hepatic BA synthesis and lipogenesis, eventually leading to liver cholestasis and steatosis. Furthermore, we found that mice that received FMT from BPA-exposed mice developed hepatic steatosis, and the influences of BPA on hepatic steatosis and FXR/TGR5 signaling pathways could be eliminated by ABX treatment, confirming the role of gut microbiota in BPA effects. Collectively, our study illustrates that suppressed microbiota-BA-FXR/TGR signaling pathways may be a potential mechanism for hepatic steatosis induced by BPA, providing a new target for the prevention of BPA-induced NAFLD.

A lipidomic study: Nobiletin ameliorates hepatic steatosis through regulation of lipid alternation

Hepatic lipidome has been given emphasis for years since hepatic steatosis is the most remarkable character of nonalcoholic fatty liver diseases, an increasingly serious health issue worldwide. Nobiletin (NOB), one of the citrus flavonoids, exerted outstanding effect on lipid metabolism disorder. However, the underlying mechanism of NOB exerting effect on hepatic lipid alternation remains unclear. In this study, the animal model was built by feeding APOE−/− mice with high fat diet (HFD). The results of Oil Red O-stained liver section and the biochemical assay of lipid parameters confirmed the protective effect of NOB on hepatic steatosis and global lipid metabolism disorder in APOE−/− mice. The hepatic lipidomic study revealed a total of 958 lipids significantly altered by HFD and a total of 86, 116, 212 lipid metabolites changed by L-NOB (50 mg/kg/d NOB), M-NOB (100 mg/kg/d NOB) and H-NOB (200 mg/kg/d NOB) respectively. In the further screening analysis, an amount of 60 lipids were identified as the potential lipid markers of NOB treatment, most of which belonged to glycerophospholipids lipid categories and exhibited obvious correlation with each other and the lipid parameters related to hepatic steatosis. Taken together, our data demonstrated that glycerophospholipids metabolism played an indispensable role in the progression of hepatic steatosis and the protective effect of NOB. Besides, the modulation towards genes involved in lipid synthesis was observed after NOB administration in this study. These finding illustrated the antihepatic steatosis effect of NOB based on altering hepatic lipidome, particularly the glycerophospholipids metabolism, and provided a new insight in the pathogenesis of hepatic steatosis.

MAFLD and Celiac Disease in Children.

Celiac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten whose clinical presentation ranges from the asymptomatic form to clinical patterns characterized by multiple systemic involvement. Although CD is a disease more frequently diagnosed in patients with symptoms of malabsorption such as diarrhea, steatorrhea, weight loss, or failure to thrive, the raised rate of overweight and obesity among general pediatric and adult populations has increased the possibility to diagnose celiac disease in obese patients as well. Consequently, it is not difficult to also find obesity-related disorders in patients with CD, including "metabolic associated fatty liver disease" (MAFLD). The exact mechanisms linking these two conditions are not yet known. The going assumption is that a gluten-free diet (GFD) plays a pivotal role in determining an altered metabolic profile because of the elevated content of sugars, proteins, saturated fats, and complex carbohydrates, and the higher glycemic index of gluten-free products than gluten-contained foods, predisposing individuals to the development of insulin resistance. However, recent evidence supports the hypothesis that alterations in one of the components of the so-called "gut-liver axis" might contribute to the increased afflux of toxic substances to the liver triggering the liver fat accumulation and to the subsequent hepatocellular damage. The aim of this paper was to describe the actual knowledge about the factors implicated in the pathogenesis of hepatic steatosis in pediatric patients with CD. The presented review allows us to conclude that the serological evaluations for CD with anti-transglutaminase antibodies, should be a part of the general workup in the asymptomatic patients with "non-alcoholic fatty liver disease" (NAFLD) when metabolic risk factors are not evident, and in the patients with steatohepatitis when other causes of liver disease are excluded.

Netrin-1 attenuates hepatic steatosis via UNC5b/PPARγ-mediated suppression of inflammation and ER stress

AimsThe current study investigated whether netrin-1 can attenuate hepatic steatosis through PPARγ/autophagy-mediated suppression of inflammation and endoplasmic reticulum (ER) stress in experimental animal models. Main methodsHepatic steatosis was induced by a high-fat diet in experimental mice. Recombinant mouse netrin-1 was administered via the tail vein (1 μg/mouse, once every two days). Serum inflammatory cytokines and hepatic inflammatory and ER stress markers were determined in mice using ELISA and western blotting protocol. Key findingsWe found that netrin-1 expression was significantly increased (P < 0.05) in cultured macrophages treated with supernatants of subcutaneous adipocytes in the presence of palmitate and subcutaneous fat of obese mice. Recombinant netrin-1 treatment promoted PPARγ expression and autophagy, thereby attenuating inflammation and ER stress, lipid accumulation, and the expression of lipogenic proteins in mouse primary hepatocytes. High-fat diet (HFD) treatment increased hepatic inflammation and ER stress, causing hepatic steatosis in experimental mice. However, administration of netrin-1 reversed the effects of HFD on hepatic ER stress and lipid deposition. SignificanceThese results suggest that subcutaneous adipose macrophage-derived netrin-1 ameliorates inflammation and ER stress in the liver, which in turn alleviates hepatic steatosis by enhancing basal PPARγ/autophagy-dependent signaling. The current study sheds light on the pathogenesis of hepatic steatosis in obesity and provides a promising therapeutic approach for treating metabolic-associated fatty liver disease (MAFLD).

Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review.

The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.

DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic Steatosis.

Background & AimsNonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality whereas the pathogenic mechanism remains largely elusive. DNA N6-methyladenosine (6mA) modification is a recently identified epigenetic mark indicative of transcription in eukaryotic genomes. Here, we aimed to investigate the role and mechanism of DNA 6mA modification in NAFLD progression.MethodsDot blot and immunohistochemistry were used to detect DNA 6mA levels. Liver-specific AlkB homolog 1 (ALKBH1)-knockout mice and mice with ALKBH1 overexpression in liver were subjected to a high-fat diet or methionine choline-deficient diet to evaluate the critical role of ALKBH1-demethylated DNA 6mA modification in the pathogenesis of hepatic steatosis during NAFLD. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate molecular mechanisms underlying this process.ResultsThe DNA 6mA level was increased significantly with hepatic steatosis, while ALKBH1 expression was down-regulated markedly in both mouse and human fatty liver. Deletion of ALKBH1 in hepatocytes increased genomic 6mA levels and accelerated diet-induced hepatic steatosis and metabolic dysfunction. Comprehensive analyses of transcriptome and chromatin immunoprecipitation sequencing data indicated that ALKBH1 directly bound to and exclusively demethylated 6mA levels of genes involved in fatty acid uptake and lipogenesis, leading to reduced hepatic lipid accumulation. Importantly, ALKBH1 overexpression was sufficient to suppress lipid uptake and synthesis, and alleviated diet-induced hepatic steatosis and insulin resistance.ConclusionsOur findings show an indispensable role of ALKBH1 as an epigenetic suppressor of DNA 6mA in hepatic fatty acid metabolism and offer a potential therapeutic target for NAFLD treatment.

Up-regulation of thioesterase superfamily member 2 in skeletal muscle promotes hepatic steatosis and insulin resistance in mice.

Thioesterase superfamily member 2 (Them2) is highly expressed in liver and oxidative tissues, where it hydrolyzes long-chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/- ) are protected against diet-induced obesity, hepatic steatosis (HS), and insulin resistance (IR), liver-specific Them2-/- mice remain susceptible. The aim of this study was to test whether Them2 activity in extrahepatic oxidative tissues is a primary determinant of HS and IR. Upon observing IR and up-regulation of Them2 in skeletal, but not cardiac, muscle of high-fat-diet (HFD)-fed wild-type compared to Them2-/- mice, we created mice with Them2 specifically deleted in skeletal (S-Them2-/- ) and cardiac muscle (C-Them2-/- ), as well as in adipose tissue (A-Them2-/- ). When fed an HFD, S-Them2-/- , but not C-Them2-/- or A-Them2-/- , mice exhibited reduced weight gain and improved glucose homeostasis and insulin sensitivity. Reconstitution of Them2 expression in skeletal muscle of global Them2-/- mice, using adeno-associated virus, was sufficient to restore excess weight gain. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice contributed to protection from HFD-induced HS by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in production of skeletal muscle metabolites, including short-chain fatty acids, branched-chain amino acids, and pentose phosphate pathway intermediates, as well as in expression of myokines that modulate insulin responsiveness. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of HS and IR and implicate it as a target in the management of NAFLD.

Variations in TM6SF2, PCSK9 and PCSK7 genes and risk of hepatic steatosis after liver transplantation: a cross-sectional study

BackgroundGenetic abnormalities might have important role in pathogenesis of hepatic steatosis after liver transplantation. We aimed to investigate association between genetic variations in transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, proprotein convertase subtilisin/kexin type 9 (PCSK9) rs505151 and proprotein convertase subtilisin/kexin type 7 (PCSK7) rs2277287 with hepatic steatosis in liver transplant recipients.MethodsIn a cross-sectional study, adult (> 18 years) liver transplant recipients who were referred for their routine post-transplant follow-up between June 2018 and September 2018 were included in the study. Hepatic steatosis in transplant recipients was assessed by controlled attenuation parameter (CAP). Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) was used to study TM6SF2 rs58542926, PCSK7 rs2277287 and PCSK9 rs505151 genotypes.Results107 liver transplant recipients were included. There was no association between different genotypes of PCSK9 rs505151 and PCSK7 rs2277287 with hepatic steatosis in liver transplant recipients (P value > 0.05). The presence of TT genotype of TM6SF2 rs58542926 was higher in patients with hepatic steatosis measured by CAP after liver transplantation. In patients with moderate and severe hepatic steatosis (grade 2 and 3 steatosis), AG + GG genotypes of PCSK9 rs505151 were more prevalent than AA genotype (OR 8.667; 95% CI 1.841–40.879; P value = 0.004) compared to patients with mild steatosis (grade 1). In multivariate regression model, AG + GG genotypes of PCSK9 rs505151 were associated with moderate and severe steatosis in liver transplant recipients (OR 5.747; 95% CI 1.086–30.303; P value = 0.040).ConclusionsGenetic variations in TM6SF2 rs58542926 and PCSK9 rs505151 might be associated with hepatic steatosis in liver transplant recipients.

Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

Obesity is a serious ongoing health problem that significantly increases the incidence of nonalcoholic fatty liver disease (NAFLD). During obesity, adipose tissue dysfunction is obvious and characterized by increased fat deposition (adiposity) and chronic low-grade inflammation. The latter has been implicated to critically promote the development and progression of NAFLD, whose advanced form non-alcoholic steatohepatitis (NASH) is considered one of the most common causes of terminal liver diseases. This review summarizes the current knowledge on obesity-related adipose dysfunction and its roles in the pathogenesis of hepatic steatosis and inflammation, as well as liver fibrosis. A better understanding of the crosstalk between adipose tissue and liver under obesity is essential for the development of new and improved preventive and/or therapeutic approaches for managing NAFLD.

Low hepatic manganese concentrations in patients with hepatic steatosis – A cohort study of copper, iron and manganese in liver biopsies

Background and aimsHepatic steatosis is the most common histopathological finding on liver biopsy, with the most prevalent etiology being NAFLD. The pathogenesis of hepatic steatosis and NAFLD is multifactorial, however, studies on the importance of manganese in NAFLD are limited. We aimed to study hepatic manganese content, and other trace elements, in relation to hepatic steatosis in patients with chronic liver diseases of different etiology, mainly NAFLD. MethodsPatients with chronically elevated liver function tests underwent a diagnostic work-up, including routine blood tests and two liver biopsies. One of the biopsies was sent for histopathological evaluation, and the other for ultra-trace elemental determinations. Steatosis was graded using conventional histopathological methodology, and fat content was also quantitated in biopsy samples by measuring the steatotic area of the section using stereological point counting (SPC). Ultra-trace elemental analysis was utilized for determining manganese, iron, and copper using inductively coupled plasma sector field mass spectrometry (ICP-SFMS). Results76 patients were included in the study. Hepatic manganese concentrations in patients with steatosis were lower than in patients without hepatic steatosis (3.8 ± 1.1 vs. 6.4 ± 1.8, P < 0.001). Similar results were seen for blood manganese levels and hepatic steatosis. We found a strong inverse correlation between steatosis grade and hepatic manganese content (ρ=-0.743, P < 0.001). Also, low levels of manganese independently predicted the presence of steatosis (aOR 0.07 [95%CI: 0.01−0.63]). ConclusionPatients with NAFLD, or other CLD and concomitant hepatic steatosis, showed lower levels of hepatic manganese content with increasing grade of steatosis.

Mechanisms of hepatic steatosis formation in adolescent boys with hypoandrogenism

There has been an increase the prevalence of andrological diseases in all age groups in recent decades, including those with comorbid conditions such as pathology of the cardiovascular system and liver, which are manifestations of metabolic syndrome.Research aim: to investigate the relationship between formation of hepatic steatosis and hypoandrogenism (HA) in adolescent boys.Materials and methods. The study involved 42 adolescent boys aged 14–18 years with laboratory confirmed HA in whom total testosterone levels were less than 12.0 nmol/l. Sex hormones, gonadotropins, insulin levels, biochemical parameters of liver function, the state of free radical oxidation and antioxidant protection were determined in patients. Based on ultrasound examination adolescents with HA were divided into 2 groups: group 1 – 15 adolescents with signs of liver steatosis; group 2 – 27 adolescents with normal ultrasound parameters of a liver. The control group consisted of 38 boys of the same age with normal indicators of physical and sexual development without signs of pathology of the hepatobiliary system. Results. Individual assessment of sexual development allowed to diagnose I degree of delayed sexual development in 44.7%, II degree in 38.3% and III degree in 17.0% of adolescents. HA negatively affects the physical development of most boys (78.7%), due to short stature (40.0%), weight deficiency (20.0%) and overweight (18.7%). Factor analysis allowed to build a factor model of hepatic steatosis formation in adolescents with delayed sexual development and HA, which describes 76.0% of the sample and consists of five factors. Conclusion. Atherogenic changes of the lipid profile, androgen deficiency, insulin resistance, activation of cytolytic processes in the liver and oxidative stress formation due to a decrease in the effectiveness of antioxidant protection are important in the pathogenesis of hepatic steatosis in boys with HA. A factor model of the hepatic steatosis development in adolescent boys with HA gives grounds for the development of therapeutic and preventive measures in adolescent boys with HA and comorbid liver pathology.

6-Gingerol Ameliorates Hepatic Steatosis via HNF4α/miR-467b-3p/GPAT1 Cascade.

Background & AimsThe development of nonalcoholic fatty liver disease (NAFLD) can be modulated by microRNAs (miRNA). Dietary polyphenols modulate the expression of miRNA such as miR-467b-3p in the liver. In addition, 6-gingerol (6-G), the functional polyphenol of ginger, has been reported to ameliorate hepatic steatosis; however, the exact mechanism involved and the role of miRNA remain elusive. In this study, we assessed the role of miR-467b-3p in the pathogenesis of hepatic steatosis and the regulation of miR-467b-3p by 6-G through the hepatocyte nuclear factor 4α (HNF4α).MethodsmiR-467b-3p expression was measured in free fatty acid (FFA)-treated hepatocytes or liver from high-fat diet (HFD)-fed mice. Gain- or loss-of-function of miR-467b-3p was induced using miR-467b-3p–specific miRNA mimic or miRNA inhibitor, respectively. 6-G was exposed to FFA-treated cells and HFD-fed mice. The HNF4α/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues.ResultsWe found that miR-467b-3p was down-regulated in liver tissues from HFD-fed mice and in FFA-treated Hepa1-6 cells. Overexpression of miR-467b-3p decreased intracellular lipid accumulation in FFA-treated hepatocytes and mitigated hepatic steatosis in HFD-fed mice via negative regulation of glycerol-3-phosphate acyltransferase-1 (GPAT1). In addition, miR-467b-3p up-regulation by 6-G was observed. 6-G inhibited FFA-induced lipid accumulation and mitigated hepatic steatosis. Moreover, it increased the transcriptional activity of HNF4α, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4α/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis.ConclusionsOur findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4α/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway.

Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.

Background & AimsNonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis.MethodsWe performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis.ResultsThe expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid–treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1–6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly.ConclusionsA high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.

Role of leptin in pathogenesis of hepatic steatosis, steatohepatitis and endothelial dysfunction in obesity: literature review

According to the latest WHO data, in the world there are 2 billion adults and 381 million children and adolescents from 0 to 19 years old, who are overweight or obese. This is due to the presence of many factors affecting the occurrence and development of this disease. One of the important links in the pathogenesis of obesity is hyperleptinemia in combination with leptin resistance.&#x0D; In this article, we attempted to summarize the information on the role of leptin in the pathogenesis of obesity complications such as liver steatosis, steatohepatitis and endothelial dysfunction. Parallels have been drawn between insulin resistance and leptin resistance. The relationship of leptin and insulin was analyzed, and data on the effect of these hormones on carbohydrate and fat metabolism are also presented.

Peripancreatic adipose tissue protects against high-fat-diet-induced hepatic steatosis and insulin resistance in mice

Background/objectivesVisceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice.Subjects/methodsFour adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4–5/group), cellular composition (FACS analysis, n = 5–6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6–10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5–11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8–10/group).ResultsWe found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many “non-adipocytes” such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05).ConclusionsPAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

Circulating IGFBP-2 levels are inversely associated with the incidence of nonalcoholic fatty liver disease: A cohort study.

ObjectiveThe insulin-like growth factor (IGF) axis is essential for the body’s metabolism. The hepatokine, insulin-like growth factor-binding protein 2 (IGFBP-2), acts as a major regulator of this metabolism. We aimed to evaluate the role of serum IGFBP-2 in the incidence of nonalcoholic fatty liver disease (NAFLD).MethodsThis hospital-based prospective cohort study recruited residents from a health program from January to November 2013, and re-invited them for follow-up in 2016. The occurrence of NAFLD was noted and IGFBP-2 levels were evaluated by enzyme-linked immunosorbent assay at both visits.ResultsOf 763 participants at baseline, 296 completed the re-evaluation. Baseline serum IGFBP-2 levels were significantly lower in subjects with NAFLD compared with those without NAFLD. Circulating IGFBP-2 levels were negatively correlated with body mass index, waist-to-hip ratio, alanine transaminase, triglycerides, fasting glucose, and insulin. IGFBP-2 levels at follow-up decreased in subjects who developed NAFLD compared with those who did not. Higher circulating levels of IGFBP-2 at baseline were negatively associated with the incidence of NAFLD.ConclusionThese results indicate that IGFBP-2 levels are inversely associated with the risk of NAFLD. This offers new insights into the role of circulating IGFBP-2, as an IGF-axis hepatokine, in the pathogenesis of hepatic steatosis.

Hepatic steatosis and liver fat contents in liver transplant recipients are associated with serum adipokines and insulin resistance

Our data about pathogenesis of hepatic steatosis after liver transplantation is scarce. This study aimed to investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients. We investigated the association between insulin resistance, serum adiponectin, insulin, and leptin with hepatic steatosis in a cohort of liver transplant recipients. Homeostatic model assessment of insulin resistance 2 (HOMA 2-IR) was used for estimation of insulin resistance. Hepatic steatosis was determined using ultrasound and controlled attenuation parameter (CAP). A total of 178 patients were included. 79 patients (44.4%) had hepatic steatosis. Serum adiponectin (OR: 0.912; 95% CI 0.869–0.957; P < 0.001), serum leptin (OR: 1.060; 95% CI 1.017–1.102; P = 0.005), HOMA2-IR (OR: 1.671; 95% CI 1.049–2.662; P = 0.031), and post-transplant diabetes mellitus (PTDM) (OR: 5.988; 95% CI 1.680–21.276; P = 0.006) were independently associated with hepatic steatosis after liver transplantation. CAP values were negatively correlated with serum adiponectin (P = 0.011) and positively correlated with serum insulin (P = 0.001), leptin (P < 0.001) and HOMA2-IR (P < 0.001). Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes.

Plasma Lipidome, PNPLA3 polymorphism and hepatic steatosis in hereditary hemochromatosis

BackgroundHereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH.MethodsWe conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination.ResultsHH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis.ConclusionOur study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.