Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

BACKGROUND: Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. METHODS: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. RESULTS: Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. CONCLUSIONS: We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

The Effect of Ultrasonic Liposuction Energy Levels on Fat Graft Viability.

BACKGROUND: The use of fat obtained from ultrasound-assisted liposuction is popular. However, no study has considered the effect of different energy levels on fat grafts. OBJECTIVES: We hypothesized that different ultrasonic energy levels could change the fat graft viability. METHODS: Both flanks of 15 CD1 nude mice (30 experimental areas) were used, with experimental areas randomly distributed into five groups. Using different energy settings, fat grafts were obtained from a patient's abdominoplasty material and applied to the mouse flank regions. Device settings were intermittent mode with 50% vibration amplitude in group 1, continuous mode with 50% vibration amplitude in group 2, intermittent mode with 90% vibration amplitude in group 3, and continuous mode with 90% vibration amplitude in group 4. The control group was grafted with fat obtained via the conventional method. After 6 weeks, all mice were sacrificed, and fat grafts were excised. Sections were stained with hematoxylin-eosin, Masson's trichrome, and anti-perilipin A antibody. RESULTS: The perilipin A immunostaining result was lowest in group 4, indicating the lowest viable cell count (p < 0.01). There was no significant difference between groups for the other parameters (p > 0.05). CONCLUSION: High ultrasonic energy may affect fat graft survival. If fat injection is planned, avoiding high energy settings (our recommendation is not to exceed 16 Watts.) should be considered. We also recommend increasing the vibration amplitude rather than switching from intermittent to continuous mode in body parts that are relatively resistant to liposuction. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Metformin Inhibits Lipid Droplets Fusion and Growth via Reduction in Cidec and Its Regulatory Factors in Rat Adipose-Derived Stem Cells.

Metformin is still being investigated due to its potential use as a therapeutic agent for managing overweight or obesity. However, the underlying mechanisms are not fully understood. Inhibiting the adipogenesis of adipocyte precursors may be a new therapeutic opportunity for obesity treatments. It is still not fully elucidated whether adipogenesis is also involved in the weight loss mechanisms by metformin. We therefore used adipose-derived stem cells (ADSCs) from inguinal and epididymal fat pads to investigate the effects and mechanisms of metformin on adipogenesis in vitro. Our results demonstrate the similar effect of metformin inhibition on lipid accumulation, lipid droplets fusion, and growth in adipose-derived stem cells from epididymal fat pads (Epi-ADSCs) and adipose-derived stem cells from inguinal fat pads (Ing-ADSCs) cultures. We identified that cell death-inducing DFFA-like effector c (Cidec), Perilipin1, and ras-related protein 8a (Rab8a) expression increased ADSCs differentiation. In addition, we found that metformin inhibits lipid droplets fusion and growth by decreasing the expression of Cidec, Perilipin1, and Rab8a. Activation of AMPK pathway signaling in part involves metformin inhibition on Cidec, Perilipin1, and Rab8a expression. Collectively, our study reveals that metformin inhibits lipid storage, fusion, and growth of lipid droplets via reduction in Cidec and its regulatory factors in ADSCs cultures. Our study supports the development of clinical trials on metformin-based therapy for patients with overweight and obesity.

Discovery of analogues of non-ß oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism.

BACKGROUND AND AIMS: Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications. METHODS AND RESULTS: Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action. In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (-34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (-71% and -64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose-response efficacy. CONCLUSIONS: Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.

Thyroid hormone receptor sumoylation is required for preadipocyte differentiation and proliferation.

Thyroid hormone and thyroid hormone receptor (TR) play an essential role in metabolic regulation. However, the role of TR in adipogenesis has not been established. We reported previously that TR sumoylation is essential for TR-mediated gene regulation and that mutation of either of the two sites in TRα or any of the three sites in TRß reduces TR sumoylation. Here, we transfected TR sumoylation site mutants into human primary preadiocytes and the mouse 3T3L1 preadipocyte cell line to determine the role of TR sumoylation in adipogenesis. Reduced sumoylation of TRα or TRß resulted in fewer and smaller lipid droplets and reduced proliferation of preadipocytes. TR sumoylation mutations, compared with wild-type TR, results in reduced C/EBP expression and reduced PPARγ2 mRNA and protein levels. TR sumoylation mutants recruited NCoR and disrupted PPARγ-mediated perilipin1 (Plin1) gene expression, associated with impaired lipid droplet formation. Expression of NCoRΔID, a mutant NCoR lacking the TR interaction domain, partially "rescued" the delayed adipogenesis and restored Plin1 gene expression and adipogenesis. TR sumoylation site mutants impaired Wnt/ß-catenin signaling pathways and the proliferation of primary human preadipocytes. Expression of the TRß K146Q sumoylation site mutant down-regulated the essential genes required for canonical Wnt signal-mediated proliferation, including Wnt ligands, Fzds, ß-catenin, LEF1, and CCND1. Additionally, the TRß K146Q mutant enhanced the canonical Wnt signaling inhibitor Dickkopf-related protein 1 (DKK1). Our data demonstrate that TR sumoylation is required for activation of the Wnt canonical signaling pathway during preadipocyte proliferation and enhances the PPARγ signaling that promotes differentiation.

Tetrandrine induces lipid accumulation through blockade of autophagy in a hepatic stellate cell line.

Macroautophagy, or autophagy, is a cellular response in which unnecessary cytoplasmic components, including lipids and organelles, are self-degraded. Recent studies closely related autophagy to activation of hepatic stellate cells (HSCs), a process critical in the pathogenesis of liver fibrosis. During HSC activation, cytoplasmic lipid droplets (LDs) are degraded as autophagic cargo, and then cells express fibrogenic genes. Thus, inhibition of autophagy in HSCs is a potential therapeutic approach for attenuating liver fibrosis. We found that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra, induced lipid accumulation, a phenotype associated with quiescent HSCs, through blockade of autophagy in the rat-derived HSC line HSC-T6. Tetrandrine inhibited autophagic flux without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes (e.g., syntaxin 17). Moreover, perilipin 1, an LD-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated HSC-T6 cells. This suggests a potential role for perilipin 1 in autophagy-mediated LD degradation in HSCs. Our results identified tetrandrine as a potential tool for prevention and treatment of HSC activation.

Genetic Association Between Polycystic Ovary Syndrome and the APOA5 rs662799 and PLIN1 rs894160 Metabolic Variants in the Western Saudi Population: A Case-Control Study.

Background: Polycystic ovary syndrome (PCOS) is a common endocrinological condition affecting women of reproductive age, associated with insulin resistance and obesity. PCOS pathogenesis is complex and multifactorial, involving genetic and environmental factors. Objectives: This study aimed to determine and compare genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (APOA5; rs662799) and perilipin 1 (PLIN1; rs894160, rs1052700 and rs6496589) genes in Western Saudi women to investigate their association with PCOS and its clinical characteristics. Design and methods: This was a case-control study conducted on women with (n = 104) and without (n = 87) PCOS. The SNPs were genotyped using TaqMan genotyping assays. Results: Significant and direct associations were detected between PCOS susceptibility and APOA5 SNP rs662799 and PLIN1 SNP rs894160 (P < .001). For APOA5 SNP rs662799, women with the A allele were more likely to have PCOS (relative risk [RR] = 1.348, odds ratio [OR] = 2.313, P < .001) and hypertriglyceridaemia (OR = 17.0, P = .5) than women with the G allele. For PLIN1 SNP rs894160, women with the T allele were more likely to have PCOS than women with the C allele (RR = 8.043, OR = 7.427, P < .001). For PLIN1 SNP rs1052700, women with the TT genotype were more likely to have hyperandrogenism (OR = 29.75, P = .02) and an irregular period (OR = 0.07, P = .040) than women with the AT genotype. Conclusion: We identified novel alleles and genotypes contributing to the genetic risk of PCOS in the Western Saudi population.

Spontaneous Remission of Acquired Generalized Lipodystrophy Presenting in the Postpartum Period.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by the diffuse loss of adipose tissue resulting in hyperglycemia, severe insulin resistance, and sequelae of metabolic disease. Here, we report the case of a 32-year-old woman who developed uncontrolled hyperglycemia and significant weight loss within 2 months postpartum. Upon endocrine evaluation, she was found to have generalized loss of adiposity, hypoleptinemia, and persistent hyperglycemia despite aggressive insulin administration. Glycemic response was obtained with U-500 intramuscular insulin, pioglitazone, and metformin-sitagliptin. At 14 months postpartum, the patient achieved spontaneous remission with normoglycemia off medication and restoration of adipose tissue deposition. Autoimmune workup revealed positive antinuclear antibodies (ANA) and anti-U1-ribonucleoprotein (anti-U1-RNP) titers, suggestive of an autoimmune etiology to her condition. This case of AGL represents the first reported case of spontaneous remission and the first to develop in the postpartum period.

Perilipin 1: a systematic review on its functions on lipid metabolism and atherosclerosis in mice and humans.

The function of perilipin 1 in human metabolism was recently highlighted by the description of PLIN1 variants associated with various pathologies. These include severe familial partial lipodystrophy and early onset acute coronary syndrome. Additionally, certain variants have been reported to have a protective effect on cardiovascular diseases. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. This literature review has two primary objectives (i) to clarify the function of the PLIN1 gene in lipid metabolism and atherosclerosis by examining functional studies performed in cells (adipocytes) and mice and (ii) to understand the impact of PLIN1 variants identified in humans based on the variant's location within the protein and the type of variant (missense or frameshift). To achieve these objectives, we conducted an extensive analysis of the relevant literature on perilipin 1, its function in cellular models and mice, and the consequences of its mutations in humans. We also utilized bioinformatics tools and consulted the Human Genetics Cardiovascular Disease Knowledge Portal to enhance the pathogenicity assessment of PLIN1 missense variants.

Cadmium modulates adipocyte functions in metallothionein-null mice.

Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT(-/-)) mice, which cannot form atoxic Cd-MT complexes and are used for evaluating Cd as free ions, and wild type (MT(+/+)) mice. Cd administration more significantly reduced the adipocyte size of MT(-/-) mice than that of MT(+/+) mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT(-/-) mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes.

Perilipin-1 immunostaining improves semi-automated digital quantitation of bone marrow adipocytes in histological bone sections.

Bone marrow adipocytes (BMAds) are not just passive fillers inside the bone marrow compartment but respond to various metabolic changes. Assessment of those responses requires evaluation of the number of BMAds and their morphology for which laborious and error-prone manual histological analysis remains the most widely used method. Here, we report an alternative image analysis strategy to semi-automatically quantitate and analyse the morphology of BMAds in histological bone sections. Decalcified, formalin-fixed paraffin-embedded histological sections of long bones of Sprague-Dawley rats were stained with either haematoxylin and eosin (HE) or by immunofluorescent staining for adipocyte-specific protein perilipin-1 (PLIN1). ImageJ-based commands were constructed to detect BMAds sized 200 µm2 or larger from standardized 1 mm2 analysis regions by either classifying the background colour (HE) or the positive and circular PLIN1 fluorescent signal. Semi-automated quantitation strongly correlated with independent, single-blinded manual counts regardless of the staining method (HE-based: r=0.85, p<0.001; PLIN1 based: r=0.95, p<0.001). The detection error was higher in HE-stained sections than in PLIN1-stained sections (14% versus 5%, respectively; p<0.001), which was due to false-positive detections of unstained adipocyte-like circular structures. In our dataset, the total adiposity area from standardised ROIs in PLIN-1-stained sections correlated with that in whole-bone sections (r=0.60, p=0.02).

Perilipin 1 Deficiency Prompts Lipolysis in Lipid Droplets and Aggravates the Pathogenesis of Persistent Immune Activation in Drosophila.

Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs' reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation.

BAP31 depletion inhibited adipogenesis, repressed lipolysis and promoted lipid droplets abnormal growth via attenuating Perilipin1 proteasomal degradation.

BAP31 expression was robustly decreased in obese white adipose tissue (WAT). To investigate the roles of BAP31 in lipid metabolism, adipocyte-specific conditional knockout mice (BAP31-ASKO) were generated. BAP31-ASKO mice grow normally as controls, but exhibited reduced lipid accumulation in WAT. Histomorphometric analysis reported increased adipocyte size in BAP31-ASKO mice. Mouse embryonic fibroblasts (MEFs) were induced to differentiation to adipocytes, showed reduced induction of adipogenic markers and attenuated adipogenesis in BAP31-deficient MEFs. BAP31-deficiency inhibited fasting-induced PKA signaling activation and the fasting response. ß3-adrenergic receptor agonist-induced lipolysis also was reduced, accompanied by reduced free-fatty acids and glycerol release, and impaired agonist-induced lipolysis from primary adipocytes and adipose explants. BAP31 interacts with Perilipin1 via C-terminal cytoplasmic portion on lipid droplets (LDs) surface. Depletion of BAP31 repressed Perilipin1 proteasomal degradation, enhanced Perilipin1 expression and blocked LDs degradation, which promoted LDs abnormal growth and supersized LDs formation, resulted in adipocyte expansion, thus impaired insulin signaling and aggravated pro-inflammation in WAT. BAP31-deficiency increased phosphatidylcholine/phosphatidylethanolamine ratio, long chain triglycerides and most phospholipids contents. Overall, BAP31-deficiency inhibited adipogenesis and lipid accumulation in WAT, decreased LDs degradation and promoted LDs abnormal growth, pointing the critical roles in modulating LDs dynamics and homeostasis via proteasomal degradation system in adipocytes.

Effect of Crocetin on Basal Lipolysis in 3T3-L1 Adipocytes.

Crocetin (CCT) is a natural saffron-derived apocarotenoid that possesses healthy properties such as anti-adipogenic, anti-inflammatory, and antioxidant activities. Lipolysis is enhanced in obesity and correlates with a pro-inflammatory, pro-oxidant state. In this context, we aimed to investigate whether CCT affects lipolysis. To evaluate CCT's possible lipolytic effect, 3T3-L1 adipocytes were treated with CCT10µM at day 5 post-differentiation. Glycerol content and antioxidant activity were assessed using colorimetric assays. Gene expression was measured using qRT-PCR to evaluate the effect of CCT on key lipolytic enzymes and on nitric oxide synthase (NOS) expression. Total lipid accumulation was assessed using Oil Red O staining. CCT10µM decreased glycerol release from 3T3-L1 adipocytes and downregulated adipose tissue triglyceride lipase (ATGL) and perilipin-1, but not hormone-sensitive lipase (HSL), suggesting an anti-lipolytic effect. CCT increased catalase (CAT) and superoxide dismutase (SOD) activity, thus showing an antioxidant effect. In addition, CCT exhibited an anti-inflammatory profile, i.e., diminished inducible NOS (NOS2) and resistin expression, while enhanced the expression of adiponectin. CCT10µM also decreased intracellular fat and C/EBPα expression (a transcription factor involved in adipogenesis), thus revealing an anti-adipogenic effect. These findings point to CCT as a promising biocompound for improving lipid mobilisation in obesity.

Dietary polyphenols and their relationship to the modulation of non-communicable chronic diseases and epigenetic mechanisms: A mini-review.

Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

The effect of omentectomy on the blood levels of adipokines in obese patients with endometrial cancer.

OBJECTIVE: To investigate the blood levels of adipokines in obese patients with endometrial cancer who have and have not undergone omentectomy. METHODS: Between September 2017 and September 2019, the study recruited 54 patients with endometrial cancer. Measurements were taken of blood levels of human leptin, perilipin-1, adiponectin, adipolin, resistin, visfatin, and estrone preoperatively and postoperatively before adjuvant therapy or at the end of one month. The serum samples were separated by centrifugation for 10 mins at 3,000 revolutions/min, then stored at -80 °C until assay. RESULTS: In this prospective study, a total of 54 endometrial cancer patients were analyzed in two separate groups according to the omentectomy status. Comprehensive staging surgery with omentectomy and without omentectomy was performed in 26 patients and 28 patients, respectively. The age, body mass index, body fat index, waist circumference, and skin thickness values of the patients with and without omentectomy were found to be similar. No statistically significant difference was determined between the patients with and without omentectomy in respect of the blood level of the adipokines measured preoperatively. A strong statistically significant correlation was determined between the pre and postoperative levels of Human Leptin (p = 0.002), perilipin-1(p = 0.001), adipolin (p < 0.001), adiponectin (p < 0.001), resistin (p = 0.001), visfatin (p < 0.001), and estrone (p = 0.004) (r = -0.43, -0.47, 0.75, 0.84, -0.47, - 0.58, -0.41, respectively) CONCLUSIONS: Omentectomy affected the postoperative blood levels of adipokines in obese patients with endometrial cancer. As omentectomy may have some positive effects on metabolism in these patients, it may be considered during endometrial cancer surgery due to the possible positive metabolic effects.

Effects of PLIN1 Gene Knockout on the Proliferation, Apoptosis, Differentiation and Lipolysis of Chicken Preadipocytes.

Perilipin 1 (PLIN1) is one of the most abundant lipid droplet-related proteins on the surface of adipocytes. Our previous results showed that PLIN1 plays an important role in chicken lipid metabolism. To further reveal the role of PLIN1 in the growth and development of adipocytes, a chicken preadipocyte line with a PLIN1 gene knockout was established by the CRISPR/Cas9 gene editing technique, and the effects of the PLIN1 gene on the proliferation, apoptosis, differentiation and lipolysis of chicken preadipocytes were detected. The results showed that the CRISPR/Cas9 system effectively mediated knockout of the PLIN1 gene. After the deletion of PLIN1, the differentiation ability and early apoptotic activity of chicken preadipocytes decreased, and their proliferation ability increased. Moreover, knockout of PLIN1 promoted chicken preadipocyte lipolysis under basal conditions and inhibited chicken preadipocyte lipolysis under hormone stimulation. Taken together, our results inferred that PLIN1 plays a regulatory role in the process of proliferation, apoptosis, differentiation and lipolysis of chicken preadipocytes.

Aquaglyceroporins and orthodox aquaporins in human adipocytes.

Aquaporins play a crucial role in water homeostasis in the human body, and recently the physiological importance of aquaporins as glycerol channels have been demonstrated. The aquaglyceroporins (AQP3, AQP7, AQP9 and AQP10) represent key glycerol channels, enabling glycerol flux across the membranes of cells. Adipocytes are the major source of glycerol and during lipolysis, glycerol is released to be metabolized by other tissues through a well-orchestrated process. Here we show that both AQP3 and AQP7 bind to the lipid droplet protein perilipin 1 (PLIN1), suggesting that PLIN1 is involved in the coordination of the subcellular translocation of aquaglyceroporins in human adipocytes. Moreover, in addition to aquaglyceroporins, we discovered by transcriptome sequencing that AQP1 is expressed in human primary adipocytes. AQP1 is mainly a water channel and thus is thought to be involved in the response to hyper-osmotic stress by efflux of water during hyperglycemia. Thus, this data suggests a contribution of both orthodox aquaporin and aquaglyceroporin in human adipocytes to maintain the homeostasis of glycerol and water during fasting and feeding.

Genetic Association between Different Metabolic Variants in APOA5 and PLIN1 in Type 2 Diabetes Mellitus among the Western Saudi Population: Case-Control Study.

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a high global incidence. Hypertriglyceridemia is a major risk factor for both cardiovascular disease and T2DM. In this study, we determined the allele and genotype frequencies of apolipoprotein A5 (APOA5) single nucleotide polymorphism (SNP) rs662799 and perilipin 1 (PLIN1) SNPs rs894160, rs6496589, and rs1052700 and evaluated their association with T2DM risk in western Saudis. Only rs6496589 was found to be significantly associated with T2DM risk. We determined the risk allele for each SNP based on relative risk, and found that the G allele of rs662799, T allele of rs894160, G allele of r6496589, and T allele of rs1052700 correlated with T2DM risk. The effect of each SNP on T2DM risk and five of its clinical phenotypes was explored using multiple logistic regression. We found significant correlations between the C/G and G/G genotypes of rs6496589 and T2DM risk in the unadjusted model, whereas G/G was the only genotype that correlated with the risk of T2DM in the adjusted model. There was no significant correlation between rs662799, rs894160, and rs1052700 genotypes and T2DM risk. In conclusion, we have identified novel risk alleles and genotypes that contribute to genetic risk for T2DM in the western Saudi population.

The diabetogenic effects of chronic supplementation of vitamin C or E in rats: Interplay between liver and adipose tissues transcriptional machinery of lipid metabolism.

AIM: The chronic administration of vitamin C and E can differentially disrupt hepatic insulin molecular pathway in rats. Hence, this study evaluated their effects on lipogenesis in the liver and adipose tissue and investigated the possible involvement of microRNA (miR)-22/29a/27a in the induced impaired glucose tolerance. MAIN METHODS: Wistar rats were orally supplemented with vitamin C (100, 200, and 500 mg/kg) or vitamin E (50, 100, and 200 mg/kg) for eight months. KEY FINDINGS: Vitamin C or E at the highest doses significantly altered liver weight and index, serum and hepatic lipids, adiponectin, and liver enzymes; besides their reported unfavorable effect on glucose homeostasis. Vitamin C and E negatively affected peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), sterol regulatory element-binding protein (SREBP)-1c/-2, miR-22/29a/27a expression, and adipose perilipin 1 to different extents, effects that were supported by the histopathological examination. SIGNIFICANCE: The current study provides a deeper insight into the findings of our previous study and highlights the detrimental effects of chronic vitamins supplementation on lipid metabolism. Overall, these findings emphasize the damage caused by the mindless use of supplements and reinforce the role of strict medical monitoring, particularly during the new COVID-19 era during which numerous commercial supplements are claiming to improve immunity.