Proteomic and lipidomic analysis of the mechanism underlying astragaloside IV in mitigating ferroptosis through hypoxia-inducible factor 1α/heme oxygenase 1 pathway in renal tubular epithelial cells in diabetic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored. AIM OF THE STUDY: To elucidate the specific mechanism by which AS-IV moderates DKD progression. MATERIALS AND METHODS: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods. RESULTS: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells. CONCLUSIONS: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.

Sitagliptin alleviates renal steatosis and endoplasmic reticulum stress in high fat diet-induced obese rats by targeting SREBP-1/CD36 signaling pathway.

High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD.

Increased FGF-21 Improves Ectopic Lipid Deposition in the Liver and Skeletal Muscle.

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

6-Gingerol alleviates ectopic lipid deposition in skeletal muscle by regulating CD36 translocation and mitochondrial function.

Ectopic lipid deposition (ELD) and mitochondrial dysfunction are common causes of metabolic disorders in humans. Consuming too much fructose can result in mitochondrial dysfunction and metabolic disorders. 6-Gingerol, the main component of ginger (Zingiber officinale Roscoe), has been proven to alleviate metabolic disorders. This study seeks to examine the effects of 6-gingerol on metabolic disorders caused by fructose and uncover the underlying molecular mechanisms. In this study, the results showed that 6-Gingerol ameliorated high-fructose-induced metabolic disorders. Moreover, it inhibited CD36 membrane translocation, increased CD36 expression in the mitochondria, and decreased the O-GlcNAc modification of CD36 and OGT expression in vitro and vivo. In addition, 6-Gingerol enhanced the performance of mitochondria in the skeletal muscle and boosted the respiratory capability of L6 myotubes. This study provides a theoretical basis and new insights for the development of lipid-lowering drugs in clinical practice.

Emerging insights into the roles of ANGPTL8 beyond glucose and lipid metabolism.

Angiopoietin-like protein 8 (ANGPTL8) is a secreted protein predominantly expressed in liver and adipose tissue. ANGPTL8 modulates the clearance of triglycerides (TGs) by suppressing the activity of lipoprotein lipase (LPL) within the plasma. Previous studies found that circulating ANGPTL8 levels were significantly increased in metabolic disorder-related diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Whether ANGPTL8 has a direct pathogenic role in these diseases remains to be determined. In this review, we summarize the emerging roles of ANGPTL8 in the regulation of inflammation, tumours, circulatory system-related diseases, and ectopic lipid deposition, which may provide new insights into the diverse functions of ANGPTL8 in various diseases beyond its well-established functions in glucose and lipid metabolism.

Plasma IGFBP-2 levels reveal heterogeneity in hepatic fat content in adults with excess visceral adiposity.

Lay summary: Obesity is frequently accompanied by a fatty liver. However, some individuals with high abdominal fat levels nevertheless have low levels of liver fat. Reasons for such discordant phenotypes are unclear. In this paper, we report that among asymptomatic individuals with high levels of visceral fat, low concentrations of IGFBP-2 in the circulation were associated with significantly higher hepatic fat content compared to those with high IGFBP-2 levels. We conclude that quantification of plasma IGFBP-2 concentrations may be useful to identify the early risk for liver fat accumulation in apparently healthy individuals without cardiovascular symptoms. Aim/hypothesis: Although excess visceral adiposity (VAT) is generally associated with increased liver fat (LF), recent evidence has revealed heterogeneity in LF content among adults with visceral obesity, potentially contributing to specific differences in cardiometabolic outcomes. Reasons for such discordant VAT-LF phenotypes are largely unknown. The present study aimed at assessing whether circulating levels of insulin growth-factor binding protein-2 (IGFBP-2) could be a useful biomarker in the identification of heterogenous and discordant VAT-LF phenotypes. Methods: A sample of 308 middle-aged Caucasian apparently healthy men and women without cardiovascular symptoms were studied for the present cross-sectional analyses. Fasting plasma glucose and lipid levels were assessed and an oral glucose tolerance test was performed. Hepatic fat fraction (HFF) was measured using magnetic resonance spectroscopy whereas VAT was assessed by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants were then classified on the basis of median VAT (81 mL) and IGFBP-2 levels (233 ng/mL). Results: Individuals with high levels of VAT were characterized by higher waist circumference, lower insulin sensitivity, as well as by higher plasma triglyceride and lower HDL-cholesterol levels. Plasma IGFBP-2 levels were inversely correlated with HFF (r = -0.39, p < 0.0001). Among men and women with high levels of VAT, those with low levels of IGFBP-2 had significantly higher HFF (7.5 ± 0.7%), compared to participants with high IGFBP-2 concentrations (3.2 ± 0.5%, p < 0.0001). Conclusion: In the presence of excess VAT, high IGFBP-2 concentrations are associated with low levels of LF. Although additional studies will be necessary to establish causality and further clarify the clinical implications of these observations, these findings are concordant with a novel function of IGFBP-2 in modulating susceptibility to non-alcoholic fatty liver disease (NAFLD) in the presence of visceral obesity.

Renal ectopic lipid deposition in rats with early-stage diabetic nephropathy evaluated by the MR mDixon-Quant technique: association with the expression of SREBP-1 and PPARα in renal tissue.

Background: Renal ectopic lipid deposition (ELD) plays a significant role in the development of diabetic nephropathy (DN). This study aimed to use the magnetic resonance (MR) mDixon-Quant technique to evaluate renal ELD and its association with the expression of sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor alpha (PPARα) in renal tissue. Methods: Seventy male Sprague-Dawley (SD) rats were randomly divided into experimental (n=50) and control groups (n=20). A high-fat diet combined with low-dose streptozotocin (STZ) was administered to the experimental group to establish a type 2 diabetes mellitus (T2DM) model. The rats received renal mDixon-Quant scans and blood lipid and histopathological examinations in batches after the T2DM model was established. According to the histopathological findings, the included rats were stratified into control and early DN groups. Renal fat fraction (FF), blood lipid level, the ratio of the integrated optical density of intracellular lipid droplets and the total area of all the cells (IOD/TAC), and the expression of SREBP-1 and PPARɑ in renal tissue were analyzed. Results: Compared to the controls, renal FF, IOD/TAC, the expression of SREBP-1 in renal tissue, and serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels were higher in the early DN group, while the expression of PPARɑ in renal tissue and the high-density lipoprotein (HDL) level were lower (all P values <0.001). Renal FF gradually increased with the progression of disease [r=0.810 (95% CI: 0.675-0.928), P<0.001]. Positive correlations between renal FF and each of the following: TC, TG, LDL, IOD/TAC, and the expression of SREBP-1 [r=0.479 (95% CI: 0.353-0.640, P=0.012), 0.576 (95% CI: 0.283-0.842, P=0.002), 0.441 (95% CI: 0.305-0.606, P=0.021), 0.911 (95% CI: 0.809-0.964, P<0.001) and 0.800 (95% CI: 0.640-0.910, P<0.001), respectively] and negative correlations between renal FF and each of the following: HDL and the expression of PPARɑ [r=-0.611 (95% CI: -0.809 to -0.469, P=0.001) and -0.748 (95% CI: -0.886 to -0.585, P<0.001), respectively] were found. Conclusions: Renal lipid deposition evaluated by the MR mDixon-Quant technique is associated with the blood lipid level, histological fat quantification, and the expression of SREBP-1 and PPARɑ in renal tissue. The renal FF value might serve as a biomarker for better understanding of renal lipid metabolism in early-stage DN.

Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment.

OBJECTIVES: Insulin resistance is associated with ectopic lipid deposition. Growth hormone (GH) status also modulates ectopic lipid accumulation, but how this associates with insulin resistance in patients with GH disorders is not well established. DESIGN AND METHODS: Twenty-one patients diagnosed with acromegaly and 12 patients with adult GH deficiency (GHD) were studied at diagnosis and after treatment. A reference group of 12 subjects was included. Each study day comprised assessment of body composition with dual-energy X-ray absorptiometry, ectopic lipid deposition in the liver by MR spectroscopy, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Disease control of acromegaly decreased lean body mass (LBM) (P < .000) and increased the percentage of total body fat (TBF) (P < .000). GH replacement increased LBM in the GHD patients (P = .007) and decreased the percentage of TBF (P = .010). The intrahepatic lipid (IHL) content increased after disease control in acromegaly (P = .004), whereas IHL did not change significantly after GH replacement in GHD (P = .34). Insulin resistance (HOMA-IR) improved after disease control of acromegaly (P < .000) and remained unaltered after GH replacement in the GHD patients (P = .829). CONCLUSIONS: GH status is a significant modulator of body composition and insulin sensitivity.GH excess reduces total fat mass and intrahepatic lipid content together with induction of insulin resistance.The data support the notion that GH-induced insulin resistance is unassociated with hepatic lipid accumulation.

The ameliorating effects of metformin on disarrangement ongoing in gastrocnemius muscle of sarcopenic and obese sarcopenic mice.

Sarcopenia and obese sarcopenia are increasingly prevalent chronic diseases with multifactorial pathogenesis, and no approved therapeutic drug to date. In the established sarcopenic mice models, muscle weakness, ectopic lipid deposition, and inflammatory responses in both serum and gastrocnemius muscle were observed, which were even deteriorated in obese sarcopenic models. With metformin intervention for 5 months, metformin exhibited benefits and restoring effects on gastrocnemius muscle of sarcopenic mice, but less effective on that of obese sarcopenic mice, as reflected in the increased percentage of muscle mass and enlarged fiber cross-sectional area, enhanced grip strength and exercise capacities, as well as the ameliorated ectopic lipid deposition and partially restored level of TNF-α, IL-1ß, IL-6, MCP-1 and IL-1α, which may be via the activation of phospho-AMPKα (Thr172). The significant up-regulated mRNA and protein level of lipolysis related proteins like hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) may contribute to the ameliorated ectopic lipid deposition with metformin intervention. The uptake of free fatty acid may be also inhibited in obese sarcopenic mice with metformin administration, as reflected in down-regulated mRNA and protein level of fatty acid transporter CD36. Furthermore, NF-κB signaling pathway was involved in the anti-inflammatory effect of metformin. These findings suggest that metformin treatment may be conducive to the prevention of age-related sarcopenia by regulating lipid metabolism in skeletal muscle, i.e. enhanced lipolysis and attenuated hyper-inflammatory responses, which may be AMPK-dependent processes. Moreover, high-fat diet would aggravate the damage to ageing in skeletal muscles and reduced their reactivity to metformin.

Pterostilbene, a Resveratrol Derivative, Improves Ectopic Lipid Deposition in the Kidneys of Mice Induced by a High-Fat Diet.

BACKGROUND: Diabetic kidney disease is a major cause of global end-stage renal diseases. Ectopic lipid deposition in the renal tissues of diabetic kidney disease is one major factor leading to renal fibrosis and chronic kidney disease. Pterostilbene has been reported to display lipid-lowing activity and participate in many kidney diseases. However, the influence of pterostilbene on the ectopic lipid deposition is unclear. We intend to explore the influence of pterostilbene on the ectopic lipid deposition in the kidneys of mice induced by high fat. METHODS: A high-fat diet-induced diabetic mouse model was established to detect the alleviative effect of pterostilbene on the ectopic lipid deposition in the kidneys of diabetic mice. A biochemical analysis was performed to examine the levels of urine albumin, urine creatinine, serum creatinine, and blood urea nitrogen in mice after pterostilbene treatment. Histological analysis was conducted to detect the degree of renal injury and fibrosis. Oil red O staining and immunohistochemical staining were carried out to evaluate lipid droplets and the expression of adipose differentiation-related protein in renal tissues of the mice treated by pterostilbene. The protein levels were assessed by Western blotting. RESULTS: Pterostilbene inhibits the expression of the TGF-ß1 and p-smad3 and suppresses the protein levels of SREBP-1 and FAS, and it ultimately reduces the ectopic lipid deposition, alleviates the renal tubular damage and renal fibrosis in the kidneys of diabetic mice induced by high fat, and improves kidney function. CONCLUSION: Pterostilbene alleviates renal fibrosis and ectopic lipid deposition in the kidneys of diabetic mice induced by high-fat diet by inhibiting the TGF-ß1/smad3 signaling.

Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague–Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells. (AU)

Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention.

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague-Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study.

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.

Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications.

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as "lipotoxicity." Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.

Inflammatory stress promotes the development of obesity-related chronic kidney disease via CD36 in mice.

Ectopic fat located in the kidney has emerged as a novel cause of obesity-related chronic kidney disease (CKD). In this study, we aimed to investigate whether inflammatory stress promotes ectopic lipid deposition in the kidney and causes renal injury in obese mice and whether the pathological process is mediated by the fatty acid translocase, CD36. High-fat diet (HFD) feeding alone resulted in obesity, hyperlipidemia, and slight renal lipid accumulation in mice, which nevertheless had normal kidney function. HFD-fed mice with chronic inflammation had severe renal steatosis and obvious glomerular and tubular damage, which was accompanied by increased CD36 expression. Interestingly, CD36 deficiency in HFD-fed mice eliminated renal lipid accumulation and pathological changes induced by chronic inflammation. In both human mesangial cells (HMCs) and human kidney 2 (HK2) cells, inflammatory stress increased the efficiency of CD36 protein incorporation into membrane lipid rafts, promoting FFA uptake and intracellular lipid accumulation. Silencing of CD36 in vitro markedly attenuated FFA uptake, lipid accumulation, and cellular stress induced by inflammatory stress. We conclude that inflammatory stress aggravates renal injury by activation of the CD36 pathway, suggesting that this mechanism may operate in obese individuals with chronic inflammation, making them prone to CKD.

Perilipin 2 and Age-Related Metabolic Diseases: A New Perspective.

Perilipin 2 (Plin2), a protein associated with the metabolism of intracellular lipid droplets (LDs), has long been considered only for its role in lipid storage. However, the manipulation of its expression affects the severity of a variety of metabolic and age-related diseases, such as fatty liver, insulin resistance and type 2 diabetes (T2D), cardiovascular disease, atherosclerosis, sarcopenia, and cancer, suggesting that this protein may play a role in these pathological conditions. In particular, its downregulation in mice prevents or mitigates some of the above mentioned diseases. Conversely, in humans high levels of Plin2 are present in sarcopenia, hepatic steatosis, atherosclerosis, and some types of cancer. We propose that inhibition of Plin2 might be a strategy to counteract several metabolic and age-related diseases.

The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis.

Non-alcoholic Fatty Liver Disease (NAFLD) is becoming the leading cause of chronic liver injury in developed countries and China. Chronic systemic inflammation plays a decisive role and is fundamental in the progression of NAFLD from simple steatosis (SS) toward higher risk nonalcoholic steatohepatitis (NASH) states. However, the exact mechanisms by which inflammation leading to NASH are incompletely understood. In this review, we focus the role of the cross talk between inflammation and lipid homeostasis on the progression of NAFLD.

Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis.

BACKGROUND: Obesity, an inflammatory condition linked to cardiovascular disease, is associated with expansion of adipose tissue. Highly prevalent coplanar polychlorinated biphenyls (PCBs) such as 3,3',4,4'-tetrachlorobiphenyl (PCB-77) accumulate in adipose tissue because of their lipophilicity and increase with obesity. However, the effects of PCBs on adipocytes, obesity, and obesity-associated cardiovascular disease are unknown. OBJECTIVES: In this study we examined in vitro and in vivo effects of PCB-77 on adipocyte differentiation, proinflammatory adipokines, adipocyte morphology, body weight, serum lipids, and atherosclerosis. METHODS: PCB-77 or 2,2',4,4,5,5'-hexachlorobiphenyl (PCB-153) was incubated with 3T3-L1 adipocytes either during differentiation or in mature adipocytes. Concentration-dependent effects of PCB-77 were contrasted with those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For in vivo studies, we treated C57BL/6 wild-type (WT) or aryl hydrocarbon receptor (AhR)(-/-) mice with vehicle or PCB-77 (49 mg/kg, by intraperitoneal injection) and examined body weight gain. In separate studies, we injected ApoE(-/-) mice with vehicle or PCB-77 over a 6-week period and examined body weight, adipocyte size, serum lipids, and atherosclerosis. RESULTS: Low concentrations of PCB-77 or TCDD increased adipocyte differentiation, glycerol-3-phosphate dehydrogenase activity, and expression of peroxisome proliferator-activated receptor gamma, whereas higher concentrations inhibited adipocyte differentiation. Effects of PCB-77 were abolished by the AhR antagonist alpha-naphthoflavone. PCB-77 promoted the expression and release of various proinflammatory cytokines from 3T3-L1 adipocytes. Administration of PCB-77 increased body weight gain in WT but not AhR(-/-) mice. ApoE(-/-) mice injected with PCB-77 exhibited greater body weight, adipocyte hypertrophy, serum dyslipidemia, and augmented atherosclerosis. CONCLUSIONS: Our findings suggest that PCB-77 may contribute to the development of obesity and obesity-associated atherosclerosis.