Ectopic Lipid Accumulation In Liver Research Articles

1379-P: Combination of FGF21 and ß3-Adrenergic Treatment in Obese Mice

An induction of lipolysis by β3-adrenergic agonist CL316,243 (CL) increases plasma free fatty acid (FFA) level resulting later in ectopic lipid accumulation in liver. The peak of FFA stimulates insulin secretion and causes acute drop of blood glucose (BG) in chow-fed mice. This glucose-lowering effect is attenuated in insulin-resistant dietary obese (DIO) mice. Fibroblast growth factor 21 (FGF21) treatment increases insulin sensitivity while inhibiting lipolysis. Both FGF21 and CL induce uncoupling protein 1 (UCP1) in brown adipose tissue, increasing capacity for combustion of glucose. Thus, the FGF21 treatment has a potential to modulate the glucoregulatory action of CL. Here we aim to characterize the effect of the CL+FGF21 combination and to investigate the role of UCP1 in this effect. DIO C57Bl/6 mice were housed at 30 °C in order to minimize basal adrenergic tone. Animals were treated 2x daily with 65 μg FGF21 or its vehicle for 8 days. This treatment lowered insulin (increased insulin sensitivity) . Subsequently, the mice were injected with 35 μg CL or with saline. CL increased FFA and insulin in control mice, but did not affect BG (probably because of impaired insulin sensitivity) . The day after CL injection, 4-fold rise in ectopic lipid content in liver was observed in comparison to saline-treated group. In FGF21-treated mice, the CL-induced rise of NEFA and insulin was only transient, but sufficient to cause a drop of BG. The hepatic lipid accumulation after CL was completely preveted by FGF21. The same experimental set-up was repeated in DIO UCP1+/+ and -/- mice. Although the BG-lowering effect of the CL+FGF21combination was observed in both genotypes, the effect was significantly stronger in UCP1+/+. Thus, FGF21 sensitizes DIO mice to the BG-lowering effect of adrenergic stimulation while it prevents ectopic lipid accummulation. The drop of BG is observed even in the absence of UCP1, but UCP1 activity is required to reach the maximal BG-lowering effect of the combination. Disclosure P.Zouhar: None. Funding Czech Science Foundation (19-05356Y)

Insulin Resistance: From Mechanisms to Therapeutic Strategies.

Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome.

Obesity causes various health problems, such as type 2 diabetes, non-alcoholic fatty liver disease, and cardio- and cerebrovascular diseases. Metabolic organs, particularly white adipose tissue (WAT) and liver, are deeply involved in obesity. WAT contains many adipocytes with energy storage capacity and secretes adipokines depending on the obesity state, while liver plays pivotal roles in glucose and lipid metabolism. This review outlines and underscores the relationship between obesity and lysosomal functions, including lysosome biogenesis, maturation and activity of lysosomal proteases in WAT and liver. It has been revealed that obesity-induced abnormalities of lysosomal proteases contribute to inflammation and cellular senescence in adipocytes. Previous reports have demonstrated obesity-induced ectopic lipid accumulation in liver is associated with abnormality of lysosomal proteases as well as other lysosomal enzymes. These studies demonstrate that lysosomal dysfunction in WAT and liver underlies part of the obesity-related pathology, raising the possibility that strategies to modulate lysosomal function may be effective in preventing or treating the metabolic syndrome.

Reduced hepatocellular lipid accumulation and energy metabolism in patients with long standing type 1 diabetes mellitus

The prevalence of obesity and metabolic syndrome increases in patients with type 1 diabetes mellitus (T1DM). In the general population this is linked with ectopic lipid accumulation in liver (HCL) and skeletal muscle (IMCL), representing hallmarks in the development of insulin resistance. Moreover, hepatic mitochondrial activity is lower in newly diagnosed patients with T1DM. If this precedes later development of diabetes related fatty liver disease is currently not known. This study aims to investigate energy metabolism in liver (kATP) and skeletal muscle (kCK) and its impact on HCL, IMCL, cardiac fat depots and heart function in 10 patients with long standing T1DM compared to 11 well-matched controls by 31P/1H magnetic resonance spectroscopy. HCL was almost 70% lower in T1DM compared to controls (6.9 ± 5% vs 2.1 ± 1.3%; p = 0.030). Also kATP was significantly reduced (0.33 ± 0.1 s−1vs 0.17 ± 0.1 s−1; p = 0.018). In T1DM, dose of basal insulin strongly correlated with BMI (r = 0.676, p = 0.032) and HCL (r = 0.643, p = 0.045), but not with kATP. In the whole cohort, HCL was significantly associated with BMI (r = 0.615, p = 0.005). In skeletal muscle kCK was lower in patients with T1DM (0.25 ± 0.05 s−1vs 0.31 ± 0–04 s−1; p = 0.039). No significant differences were found in IMCL. Cardiac fat depots as well as heart function were not different. Our results in patients with long standing T1DM show that HCL is lower compared to matched controls, despite reduced energy metabolism in liver and skeletal muscle.

Clinical implication of ectopic liver lipid accumulation in renal cell carcinoma patients without visceral obesity

Fatty liver has emerged as a prognostic marker of cancer, so we investigated the impact of ectopic lipid accumulation in liver on the clinical outcome for patients with renal cell carcinoma (RCC). The records of 230 consecutive patients who had undergone surgery for RCC were reviewed, and liver lipid accumulation was estimated from the attenuation in unenhanced preoperative CT images. The median liver CT values of patients with G3 tumors was lower than that of patients with G1–2 tumors (P = 0.0116), that of patients with pT3–4 tumors was lower than that of patients with pT1–2 tumors (P = 0.0336), and that of patients with visceral obesity defined as a visceral fat area ≥ 100 cm2 was lower than that of patients without visceral obesity (P < 0.0001). In patients without visceral obesity the median liver CT values of patients with pT3–4 tumors was lower than that of patients with pT1–2 tumors (P = 0.0401), that of patients with metastasis was lower than that of patients without metastasis (P = 0.026), and fatty liver was associated with shorter overall survival (P = 0.0009). Ectopic lipid accumulation in liver thus seems to be a predictor of aggressive forms of RCC.

An alternative model for studying age-associated metabolic complications: Senescence-accelerated mouse prone 8

Rodent animal models take at least 18months to develop aging phenotypes for researchers to investigate the mechanism of age-related metabolic complications. Senescence-accelerated mouse prone 8 (SAMP8) shortens the process of aging and may facilitate an alternative model for studying age-related insulin resistance. The short-lived strain SAMP8 and two long-lived strains SAM resistant 1 (SAMR1) mice and C57BL/6 mice at 12 (young) and 40weeks old (old) were used in the present study. Glucose tolerance test, histology and signaling pathways involved in lipid metabolism in adipose tissue and liver and key components of insulin signaling pathway in the skeletal muscle were determined in these three strains. We found that short-lived SAMP8 mice developed symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance in association with adipocyte hypertrophy and ectopic lipid accumulation in liver and muscle at 40-wk.-old. Significantly increased serum IL-6, leptin, and resistin levels and adipogenic transcription factor PPARγ and macrophage marker F4/80 mRNA expression in adipose tissues were observed in old SAMP8 mice, compared with that in young SAMP8 mice. Marked increases in SREBP1 and PPARγ and a decrease in PPARα at mRNA level in accordance with activation of mTOR/Akt pathway were contributed to hepatic lipid accumulation in old SAMP8 mice. Down-regulation of insulin signaling pathway including IRβ, IRS1, and AS160 at protein level in skeletal muscle was observed in old SAMP8 mice. At 40-wk.-old, both long-lived SAMR1 and C57BL/6 mice have not been fully developed age-related metabolic disorders including insulin resistance and visceral fat expansion in line with fewer defects in lipid metabolism and skeletal muscle insulin signaling pathway. In conclusion, our data suggest the suitability of the SAMP8 mice as a model for studying age-related metabolic complications.

Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function.

To determine the roles of insulin and insulin-like growth factor 1 (IGF-1) action in adipose tissue, we created mice lacking the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a ∼25% reduction in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas mice lacking both IR and IGF1R (F-IR/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function.

MP78-01 ECTOPIC LIPID ACCUMULATION IN LIVER IS ASSOCIATED WITH TUMOR AGGRESSIVENESS AND POOR PROGNOSIS IN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging II1 Apr 2016MP78-01 ECTOPIC LIPID ACCUMULATION IN LIVER IS ASSOCIATED WITH TUMOR AGGRESSIVENESS AND POOR PROGNOSIS IN RENAL CELL CARCINOMA Daisuke Watanabe, Akio Horiguchi, Shinsuke Tasaki, Kenji Kuroda, Akinori Satoh, Junichi Asakuma, Keiichi Ito, Tomohiko Asano, and Hiroshi Shinmoto Daisuke WatanabeDaisuke Watanabe More articles by this author , Akio HoriguchiAkio Horiguchi More articles by this author , Shinsuke TasakiShinsuke Tasaki More articles by this author , Kenji KurodaKenji Kuroda More articles by this author , Akinori SatohAkinori Satoh More articles by this author , Junichi AsakumaJunichi Asakuma More articles by this author , Keiichi ItoKeiichi Ito More articles by this author , Tomohiko AsanoTomohiko Asano More articles by this author , and Hiroshi ShinmotoHiroshi Shinmoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1957AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Obesity is a well-known risk factor for the development of renal cell carcinoma (RCC). However, the impact of BMI-indicated visceral fat distribution on tumor aggressiveness and prognosis in RCC remains controversial. Because free fatty acids are transported from excess visceral adipose tissue directly to the liver via the portal vein, the ectopic lipid accumulation in liver could be more informative as a prognostic factor for RCC. In the present study, we examined the ectopic lipid accumulation in liver in patients with RCC and investigated its associations with clinicopathological parameters and survival. METHODS A total of 230 patients who underwent surgery for RCC at a single institute were retrospectively reviewed. The mean CT values of liver regions of S3 and S6 and S8 were estimated in the preoperative planar CT images, and a fatty liver was defined as one with a mean CT value < 50 Hounsfield units. The visceral fat area (VFA) was also estimated in the preoperative planar CT images at the umbilical level, and the visceral obesity was defined as VFA ≥ 100 cm2. Kaplan-Meier curves were generated to determine overall survival (OS) rates and cancer specific survival (CSS) rates for patients, and the log rank test was used to compare the survival rates of patients with and without fatty liver. Cox proportional hazard models were used to identify the independent predictors of OS and CSS. RESULTS Visceral fat area was not associated with any pathological parameters or survival. The mean liver CT values of patients with high-grade tumors (G3), patients with T3-4 tumors, and patients with visceral obesity were significantly lower than those of patients with low-grade tumors (G1-2), patients with T1-2 tumors, and patients without visceral obesity (p = 0.0116, p = 0.0336, p < 0.0001, respectively). Overall patients with fatty liver had significantly shorter OS and CSS than those without fatty liver (p = 0.0095, p = 0.0145). In patients without visceral obesity, the mean liver CT values of patients with T3-4 tumors and patients with lymph node metastasis and/or distant metastasis at the time of operation were significantly lower than those of patients with T1-2 tumors and patients without any metastasis (p = 0.0401, p = 0.026), and presence of fatty liver was significantly associated with shorter OS and CSS (p = 0.0009, p = 0.0015). CONCLUSIONS Our results suggest that ectopic lipid accumulation in liver could be a novel predictor of tumor aggressiveness and poor prognosis in renal cell carcinoma regardless of the presence or absence of visceral obesity. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1024 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Daisuke Watanabe More articles by this author Akio Horiguchi More articles by this author Shinsuke Tasaki More articles by this author Kenji Kuroda More articles by this author Akinori Satoh More articles by this author Junichi Asakuma More articles by this author Keiichi Ito More articles by this author Tomohiko Asano More articles by this author Hiroshi Shinmoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PCB and OCP accumulation and evidence of hepatic alteration in the Atlantic bluefin tuna, T. thynnus, from the Mediterranean Sea

Persistent organic pollutants (POPs) are known to act as “obesogens”, being fat-soluble and affecting lipid metabolism. The Atlantic bluefin tuna, Thunnus thynnus, are top pelagic predators prone to bioaccumulate and biomagnify environmental contaminants. This study aimed at evaluating POPs-induced ectopic lipid accumulation in liver of adult tuna from the Mediterranean Sea. PCBs and organochlorine pesticides were measured in tuna liver, and marked morphological changes observed, namely poorly compacted tissues, intense vacuolization, erythrocyte infiltration and presence of melanomacrophages. The expression of perilipin, a lipid-droplet marker, positively correlated with the gene expression of PPARγ, a master regulator of adipogenesis, and its heterodimeric partner, RXRα. Changes in metabolites involved in fatty acid biosynthesis and ketogenesis were also observed. Although male bluefin tuna appeared to be more sensitive than females to the adverse effects of environmental obesogens, the alterations observed in tuna liver of both sexes suggest a potential onset of hepatic steatosis.

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.

Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.

1H-MRS Measured Ectopic Fat in Liver and Muscle in Danish Lean and Obese Children and Adolescents.

ObjectivesThis cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children.MethodsFasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8–18 years.ResultsIn 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed.Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol.ConclusionHepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk.

ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content

ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60–70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho­sphory­lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle.

Induction of adipocyte hyperplasia in subcutaneous fat depot alleviated type 2 diabetes symptoms in obese mice

The role of subcutaneous adipose tissue (SAT) in the pathogenesis of type 2 diabetes is still under controversy. In this study, the metabolic effects of inducing adipocyte hyperplasia in SAT depots in obese mice were investigated. High fat diet was used to induce obesity and type 2 diabetes symptoms in C57BL6/J mice. To induce SAT expansion through hyperplasia, acellular adipogenic cocktails were injected around the SAT depots in high fat diet-induced obese mice. Ten weeks after injections, significant neoadipogenesis was induced, which not only obviously expanded the volume of SATs but also significantly increased the adipocyte density within the whole SAT depots. Importantly, these mice exhibited improved glucose tolerance and insulin sensitivity (homeostatic model assessment) when compared to control group. Further studies suggested that these beneficial metabolic effects were associated with elevation of serum high-molecular-weight adiponectin level and reduction of ectopic lipid accumulation in liver. These findings not only further supported the protective role of SAT in the pathogenesis of type 2 diabetes but also highlighted the importance of adipocyte hyperplasia in this protective effect.

Chronic Peripheral Hyperinsulinemia in Type 1 Diabetic Patients After Successful Combined Pancreas-Kidney Transplantation Does Not Affect Ectopic Lipid Accumulation in Skeletal Muscle and Liver

OBJECTIVESo far it is unclear whether chronic peripheral hyperinsulinemia per se might contribute to ectopic lipid accumulation and consequently insulin resistance. We investigated the effects of systemic instead of portal insulin release in type 1 diabetic patients after successful pancreas-kidney transplantation (PKT) with systemic venous drainage on the intracellular lipid content in liver and soleus muscle, endogenous glucose production (EGP), and insulin sensitivity.RESEARCH DESIGN AND METHODSIn nine PKT patients and nine matching nondiabetic control subjects, intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) were measured using 1H nuclear magnetic resonance spectroscopy. Fasting EGP was measured using d-[6,6-2H2]glucose tracer dilution. A 3-h 75-g oral glucose tolerance test (OGTT) allowed us to assess kinetics of glucose, free fatty acids, insulin, and C-peptide concentrations in plasma and to calculate the clamp-like index (CLIX) for insulin sensitivity and the hepatic insulin resistance (HIR) index.RESULTSThe PKT patients displayed approximately twofold increased fasting insulin (20 ± 6 vs. 9 ± 3 μU/ml; P < 0.0002) compared with that in nondiabetic control subjects and ∼10% increased fasting glucose (P < 0.02) concentrations, but during the OGTT areas under the concentration curves of C-peptide and insulin were similar. IHCL (PKT, 2.9 ± 2.5%; nondiabetic control subjects, 4.4 ± 6.6%), IMCL (PKT, 1.0 ± 0.4%; nondiabetic control subjects, 1.0 ± 0.5%), CLIX (PKT, 8 ± 2; nondiabetic control subjects, 7 ± 3), HIR (PKT, 25.6 ± 13.2; nondiabetic control subjects, 35.6 ± 20 [mg · min−1 · kg−1] × [μU/ml]), and EGP (PKT, 1.6 ± 0.2; nondiabetic control subjects, 1.7 ± 0.2 mg · min−1 · kg−1) were comparable between PKT patients and nondiabetic control subjects. IHCL was negatively correlated with CLIX in all participants (r = −0.55; P < 0.04).CONCLUSIONSDespite fasting peripheral hyperinsulinemia because of systemic venous drainage, type 1 diabetic patients after PKT show similar IHCL, IMCL, insulin sensitivity, and fasting EGP in comparison with nondiabetic control subjects. These results suggest that systemic hyperinsulinemia per se does not cause ectopic lipid accumulation in liver and skeletal muscle.