Cholesterol Ester Accumulation Research Articles

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.

Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

SOAT1 regulates cholesterol metabolism to induce EMT in hepatocellular carcinoma

Cholesterol metabolism reprogramming is one of the significant characteristics of hepatocellular carcinoma (HCC). Cholesterol increases the risk of epithelial–mesenchymal transition (EMT) in cancer. Sterol O-acyltransferases 1 (SOAT1) maintains the cholesterol homeostasis. However, the exact mechanistic contribution of SOAT1 to EMT in HCC remains unclear. Here we demonstrated that SOAT1 positively related to poor prognosis of HCC, EMT markers and promoted cell migration and invasion in vitro, which was mediated by the increased cholesterol in plasmalemma and cholesterol esters accumulation. Furthermore, we reported that SOAT1 disrupted cholesterol metabolism homeostasis to accelerate tumorigenesis and development in HCC xenograft and NAFLD-HCC. Also, we detected that nootkatone, a sesquiterpene ketone, inhibited EMT by targeting SOAT1 in vitro and in vivo. Collectively, our finding indicated that SOAT1 promotes EMT and contributes to hepatocarcinogenesis by increasing cholesterol esterification, which is suppressed efficiently by nootkatone. This study demonstrated that SOAT1 is a potential biomarker and therapeutic target in NAFLD-HCC and SOAT1-targeting inhibitors are expected to be the potential new therapeutic treatment for HCC.

Otras enfermedades hepáticas de causa genética, metabólica y endocrinológica

Liver diseases of genetic origin comprise a series of diseases that manifest as abnormalities in liver structure and/or function due to genetic mutations. This update will discuss some of them, such as alpha-1 antitrypsin deficiency (A1AT), Wilson's disease, lysosomal acid lipase deficiency (LAL-D), and other congenital diseases related to bile acid and bilirubin metabolism.Alpha-1 antitrypsin deficiency is an autosomal codominant condition characterized by a decrease in secretion of alpha-1 antitrypsin protein, which acts as an inhibitor of neutrophil elastase. This results in liver and lung damage due to an accumulation of misfolded protein in hepatocytes and uncontrolled elastase activity. On the other hand, in Wilson's disease, an autosomal recessive disorder, mutations in the ATP7B gene impair copper metabolism. This results in an accumulation of toxic copper in the liver and other organs, causing hepatitis, cirrhosis, and neuropsychiatric manifestations. Lysosomal acid lipase deficiency is an autosomal recessive disorder caused by mutations in the LIPA gene. This results in the accumulation of cholesterol and triglyceride esters in lysosomes, leading to hepatomegaly, hyperlipidemia, and premature atherosclerosis. Finally, the set of diseases related to bilirubin and bile acid metabolism involve abnormalities in the production, transport, and excretion of bilirubin and bile acids. They are associated with cholestasis and hepatocellular damage, which can lead to liver failure and death.

A case report of Tangier disease presents with acute sensorimotor polyneuropathy and its treatment approach

Polyneuropathy is a frequently encountered clinical presentation where peripheral nerves are affected due to the same cause and physiopathological processes. We report a case of acute sensorimotor polyneuropathy in a patient with Tangier disease (TD) who was treated with miglustat which is a glycosphingolipid synthesis inhibitor. TD is a very rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes the cholesterol efflux regulatory protein. It leads to accumulation of cholesterol esters within various tissues and affects lipid metabolism by deficiency of high-density lipoprotein (HDL) in the blood. Due to the accumulation of cholesterol esters in Schwann cells, it could provoke polyneuropathy in TD. Our case presented to our clinic with quadriparesis and after treated with miglustat therapy his weakness regressed.

Multi‐omic profiling of isogenic ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes uncovers altered lipid metabolism and mitochondrial function of ApoE4 astrocytes

AbstractBackgroundAs the main genetic risk factor for AD, glial ApoE4 has been implicated in a number of early disease relevant processes, such as lipid dyshomeostasis, mitochondrial dysfunction and altered immune function. This ApoE4 glial phenotype is not yet well characterized and this hampers the rationale design of ApoE4‐targeting interventions.MethodWe characterize the phenotypes of ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes by multi‐omic profiling. In addition, we use lipidomic and metabolic profiling of interventions in ApoE4 astrocytes to define compounds that normalize lipid counts and metabolic function.ResultIn the ApoE4 astrocytes we observe strong accumulation of cholesterol esters (storage product of cholesterol) and triglycerides (storage products of fatty acids), in comparison to the ApoE3 astrocytes. Interestingly, our proteomic and transcriptomic profiling of these cells reveal an increase in cholesterol synthesis, despite the already high levels of cholesterol esters in the cell. Moreover, our proteomic and transcriptomic results display an increase in mitochondrial pathways, such as beta‐oxidation, TCA cycle and oxidative phosphorylation and a decrease in glycolysis. Not only mitochondrial function is altered but also mitochondrial organization, as we see an upregulation of the most relevant proteins for mitochondrial fusion, MFN1, MFN2 and OPA1. Our lipidomic and metabolic profiling of ApoE4 astrocytes after treatment with a number of different interventions reveals new insights into these altered lipid metabolic pathways.ConclusionOur multi‐omic profiling of iPSC‐derived ApoE3/3 and ApoE4/4 astrocytes uncovers that ApoE4 astrocytes have altered lipid metabolism, mitochondrial function and mitochondrial organization. Treatment with interventions reveals new insights into these altered pathways.

Drug screen identifies verteporfin as a regulator of lipid metabolism in macrophage foam cells

Arterial macrophage foam cells are filled with cholesterol ester (CE) stored in cytosolic lipid droplets (LDs). Foam cells are central players in progression of atherosclerosis as regulators of lipid metabolism and inflammation, two major driving forces of atherosclerosis development. Thus, foam cells are considered plausible targets for intervention in atherosclerosis. However, a compound that directly regulates the lipid metabolism of LDs in the arterial foam cells has not yet been identified. In this study, we screened compounds that inhibit macrophage foam cell formation using a library of 2697 FDA-approved drugs. From the foam cells generated via loading of human oxidized low-density lipoprotein (oxLDL), we found 21 and 6 compounds that reduced and enhanced accumulations of lipids respectively. Among them, verteporfin most significantly reduced oxLDL-induced foam cell formation whereas it did not display a significant impact on foam cell formation induced by fatty acid. Mechanistically our data demonstrate that verteporfin acts via inhibition of oxLDL association with macrophages, reducing accumulation of CE. Interestingly, while other drugs that reduced foam cell formation did not have impact on pre-existing foam cells, verteporfin treatment significantly reduced their total lipids, CE, and pro-inflammatory gene expression. Together, our study identifies verteporfin as a novel regulator of foam cell lipid metabolism and inflammation and a potential compound for intervention in atherosclerosis.

Cholesterol Metabolism in Pancreatic Cancer.

Pancreatic cancer's substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune suppression. Clinical trials targeting cholesterol metabolism, including statins and SOAT1 inhibitors, exhibit potential anti-tumor effects, and combination therapies enhance efficacy. This review provides insights into cholesterol metabolism's convergence with pancreatic cancer, shedding light on therapeutic avenues and ongoing clinical investigations.

Lipid Profile of the Muscle Tissue of Some Mesopelagic Fish Species of the Families Stomiidae and Myctophidae from Different Depths of the Irminger Sea, North Atlantic

For the first time the qualitative and quantitative lipid profile (total lipids and polar and nonpolar lipids) of the muscle tissue of six mesopelagic fish species, which are representatives of two deep-sea families widespread in the World Ocean: Stomiidae and Myctophidae were studied. It was found the species specificity of lipid accumulation for the studied fishes, which indicates differences in the mechanisms of compensatory responses. Triacylglycerols are the main form of lipid storage in the studied species. However, an accumulation of cholesterol esters and waxes (lipid characteristic of vertical migrants) has also been recorded in Borostomias antarcticus. The revealed distinctive features of Myctophidae and Stomiatidae, related to the accumulation of cholesterol and variations in the content of different phospholipid fractions, indicate that the fishes of these families use different mechanisms for regulating and maintaining the physicochemical state (permeability and fluidity) of biological membranes under conditions of change in a set of environmental factors (temperature, salinity, hydrostatic pressure, and specific photoperiod) with increase in the habitat depth.

Lipid Profile of the Muscle Tissue of Some Mesopelagic Fish Species of the Families Stomiidae and Myctophidae from Different Depths of the Irminger Sea, North Atlantic

For the first time the qualitative and quantitative lipid profile (total lipids and polar and nonpolar lipids) of the muscle tissue of six mesopelagic fish species, which are representatives of two deep-sea families widespread in the World Ocean: Stomiidae and Myctophidae were studied. It was found the species specificity of lipid accumulation for the studied fishes, which indicates differences in the mechanisms of compensatory responses. Triacylglycerols are the main form of lipid storage in the studied species. However, an accumulation of cholesterol esters and waxes (lipid characteristic of vertical migrants) has also been recorded in Borostomias antarcticus. The revealed distinctive features of Myctophidae and Stomiatidae, related to the accumulation of cholesterol and variations in the content of different phospholipid fractions, indicate that the fishes of these families use different mechanisms for regulating and maintaining the physicochemical state (permeability and fluidity) of biological membranes under conditions of change in a set of environmental factors (temperature, salinity, hydrostatic pressure, and specific photoperiod) with increase in the habitat depth.

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia.

Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRα-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.

Intratracheal Administration of Acyl Coenzyme A Acyltransferase-1 Inhibitor K-604 Reduces Pulmonary Inflammation Following Bleomycin-Induced Lung Injury.

Acute lung injury (ALI) is characterized by epithelial damage, barrier dysfunction, and pulmonary edema. Macrophage activation and failure to resolve play a role in ALI; thus, macrophage phenotype modulation is a rational target for therapeutic intervention. Large, lipid-laden macrophages have been observed in various injury models, including intratracheal bleomycin (ITB), suggesting that lipid storage may play a role in ALI severity. The endoplasmic reticulum-associated enzyme acyl coenzyme A acyltransferase-1 (Acat-1/Soat1) is highly expressed in macrophages, where it catalyzes the esterification of cholesterol, leading to intracellular lipid accumulation. We hypothesize that inhibition of Acat-1 will reduce macrophage activation and improve outcomes of lung injury in ITB. K-604, a selective inhibitor of Acat-1, was used to reduce cholesterol esterification and hence lipid accumulation in response to ITB. Male and female C57BL6/J mice (n = 16-21/group) were administered control, control + K-604, ITB, or ITB + K-604 on d0, control or K-604 on d3, and were sacrificed on day 7. ITB caused significant body weight loss and an increase in cholesterol accumulation in bronchoalveolar lavage cells. These changes were mitigated by Acat-1 inhibition. K-604 also significantly reduced ITB-induced alveolar thickening. Surfactant composition was normalized as indicated by a significant decrease in phospholipid: SP-B ratio in ITB+K-604 compared with ITB. K-604 administration preserved mature alveolar macrophages, decreased activation in response to ITB, and decreased the percentage mature and pro-fibrotic interstitial macrophages. These results show that inhibition of Acat-1 in the lung is associated with reduced inflammatory response to ITB-mediated lung injury.SIGNIFICANCE STATEMENTAcyl coenzyme A acyltransferase-1 (Acat-1) is critical to lipid droplet formation, and thus inhibition of Acat-1 presents as a pharmacological target. Intratracheal administration of K-604, an Acat-1 inhibitor, reduces intracellular cholesterol ester accumulation in lung macrophages, attenuates inflammation and macrophage activation, and normalizes mediators of surface-active function after intratracheal bleomycin administration in a rodent model. The data presented within suggest that inhibition of Acat-1 in the lung improves acute lung injury outcomes.

Acat‐1 Inhibition Reduces Inflammatory Response to Bleomycin‐mediated Lung Injury

Acute lung injury (ALI) is characterized by epithelial damage, barrier dysfunction, and pulmonary edema. Macrophage (MΦ) activation and failure to resolve play a role in in ALI, thus MΦ phenotype modulation is a rational target for therapeutic intervention. Large, lipid‐laden MΦs have been observed in various injury models, including intratracheal bleomycin (ITB), suggesting that lipid storage may play a role in ALI severity. The mitochondrial enzyme Acat‐1 is highly expressed in MΦs where it catalyzes the esterification of cholesterol, leading to intracellular lipid accumulation. We hypothesize that inhibition of Acat‐1 will reduce MΦ activation and reduce ITB‐mediated lung injury. K‐604, a selective inhibitor of Acat‐1, was used to reduce lipid accumulation in ITB. Male and female C57BL6/J mice (n=16‐21/group) were administered PBS, K‐604, ITB, or ITB +K‐604 on d0, PBS or K‐604 on d3, and were sacrificed on d7. ITB caused significant (*p<0.05 v PBS) body weight loss (‐13.92±2.05%* v 2.66±0.78%) and an increase in cholesterol accumulation (71.63±11.7 μM* v 15.51±9.1 μM) and size (29.67±10.6 μm* v 11±4.3 μm) of pulmonary MΦs. These changes were mitigated by Acat‐1 inhibition, as ITB+K‐604 mice had significantly (#p<0.05 v ITB) reduced body weight loss (4.04±1.03%#), cholesterol accumulation (13.79±5.4#), and MΦ diameter (14.0±3.7 μm#), confirming successful inhibition of Acat‐1 in the lung. Histological analysis showed that K‐604 significantly reduced ITB‐induced alveolar wall thickening (2.3±0.05 μm# v 4.35±0.04 μm) and reduced measures of consolidation and cell infiltration. Surface active function was normalized as indicated by a significant decrease in phospholipid:SP‐B ratio in ITB+K‐604 compared to ITB (7.95±1.22# v 13.28±2.17). K‐604 administration rescued ITB‐mediated loss of resident alveolar MΦs (CD45+/Siglec F+/F/480+, CD11c+, CD11b‐) (72.00±5.67%# v 49.58±8.52%) and was found to decrease the % of pro‐inflammatory alveolar MΦs (CD45+/Siglec F+/F/480+, Ly6c+, CD206‐) (3.86±0.88%# v 8.22±1.76%). K‐604 reduced ITB‐mediated increases in NOS2 (64.23±20.07# v 131.89±17.07) and ARG1 expression (42.39±8.14# v 177.41±52.2) in BAL MΦs, suggesting reduced inflammatory signaling and immunometabolic demand. In our ITB model, K‐604 also decreased the % of interstitial MΦs (IMs) (tissue‐derived CD45+, Siglec F ‐, F4/80+, CD11b+) expressing markers of maturity and fibrotic potential (CD11c+/CD206+) (5.89±2.15%# v 19.72±1.93%). IMs were also found to have an increased rate of lipid uptake after K‐604 regardless of ITB administration as measured by the uptake of fluorescently labeled LDL and visualization by confocal microscopy. These data, along with changes in cholesterol ester accumulation, suggest that Acat‐1 inhibition alters lipid storage and uptake within pulmonary macrophages, affecting cell phenotype and function. Thus, Acat‐1 may be a target for intervention in ALI.

The Loss of PPARα in Adipocytes Induces Lipogenesis via the PASK‐SREBP1 Signaling Axis

PPARα is a nuclear receptor and a key player in regulating adiposity by activating b‐oxidation while inhibiting de novo lipogenesis within the liver. Its role in extrahepatic tissues is currently unknown. Therefore, we established the first adipose‐specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion and adipocyte hypertrophy that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high‐fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) (p=0.0091) and brown adipose tissue (BAT) (p=0.0031) with HFD compared to littermates. No changes in adiposity were observed in female mice compared to littermate controls. Lipidomics analysis of iWAT via liquid chromatography–mass spectrometry (LC‐MS) showed that PparaFatKO males had an increase in cholesterol esters. Interrogation of the signaling mechanisms with the loss of PPARα in adipocytes showed that the transcription factor sterol regulatory element‐binding protein‐1 (SREBP‐1) had more of the mature form present in the KO males and its target genes were higher, which might be due to the significantly (p=0.009) elevated expression of the Per‐Arnt‐Sim Kinase (PASK), a kinase that activates SREBP‐1. The hyperactivity of the PASK‐SREBP‐1 axis significantly (p<0.05) increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl‐Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). Hence, we have uncovered a new signaling paradigm, the PASK‐SREBP‐1 axis in adipocytes, that drives lipogenesis, which PPARα inhibits. Our results demonstrate the first adipose‐specific actions for PPARα in protecting against lipogenesis and cholesterol ester accumulation that leads to adipocyte hypertrophy in obesity.

Differential cholesterol uptake in liver cells: A role for PCSK9.

The clearance of low-density lipoprotein (LDL) particles from the circulation is regulated by the LDL receptor (LDLR) and proprotein convertase subtilisin/kexin 9 (PCSK9) interaction. Its disruption reduces blood cholesterol levels and delays atherosclerosis progression. Whether other members of the LDLR superfamily are in vivo targets of PCSK9has been poorly explored. The aim of this work was to study the interaction between PCSK9 and members of the LDLR superfamily in the regulation of liver cholesterol homeostasis in an in vivo low-density lipoprotein receptor related protein 5 (LRP5) deficient mice model challenged with high-fat diet. Our results show that Wt and Lrp5-/- mice fed a hypercholesterolemic diet (HC) have increased cholesterol ester accumulation and decreased liver LDLR and LRP5gene and protein expression. Very low-density lipoprotein receptor (VLDLR), LRP6, LRP2, and LRP1 expression levels were analyzed in liver samples and show that they do not participate in Lrp5-/- liver cholesterol uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in liver-specific fat-storing stellate cells but not in structural HepG2 cells. Hepatic stellate cells silenced for LRP5 and/or PCSK9 expression and challenged with lipids show reduced cholesterol ester accumulation, indicating that both proteins are involved in lipid processing in the liver. Our results indicate that cholesterol esters accumulate in livers of Wt mice in a LDLR-family-members dependent manner as VLDLR, LRP2, and LRP6show increased expression in HC mice. However, this increase is lost in livers of Lrp5-/- mice, where scavenger receptors are involved in cholesterol uptake. PCSK9 expression is strongly downregulated in mice livers after HC feeding. However PCSK9 and LRP5 bind in the cytoplasm of fat storing liver cells, indicating that this PCSK9-LRP5 interaction is cell-type specific and that both proteins contribute to lipid uptake.

Lysosomal acid lipase deficiency – an underestimated cause of hypercholesterolemia in children

Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, autosomal recessive disease, which develops due to impaired degradation and subsequent intra-lysosomal accumulation of triglycerides and cholesterol esters causing dyslipidemia. The clinical manifestations of the disease presumably depend on the residual activity of the enzyme, lysosomal acid lipase. A profound deficiency of the enzyme known as Wolman’s disease has an onset in the first 6 months of life. The disease reveals itself by dyspeptic disorders in the form of vomiting and diarrhea, lack of weight gain, hepatosplenomegaly, and adrenal calcification. If the Wolman’s disease is not treated, children die within the first 6 months as a result of exhaustion caused by malabsorption syndrome combined with progressive deterioration of liver and adrenal glands. Partial deficiency of lysosomal acid lipase manifests itself at a later age and is called cholesterol ester storage disease. Its clinical presentations include hepatosplenomegaly, elevated transaminases, hypercholesterolemia, and, in some cases, hypertriglyceridemia. Liver failure is the main cause of death in the natural course of cholesterol ester storage disease. Delayed diagnosis of the disease leads to its progression causing irreversible liver damage. The implementation of mass screening programs with the determination of cholesterol levels in childhood is critical to identifying asymptomatic patients.The article presents a clinical case of a patient aged 3 years. The molecular genetic testing showed a mutation in exon 8 of the LIPA gene: NM_000235.3:c.894G>A synonymous variant in the homozygous state. It was also found that both parents of the girl had this type of mutation in the heterozygous state. The patient was prescribed sebelipase alfa in a dose of 1 mg/kg once every 14 days. The treatment was well tolerated. Due to the early verification of the diagnosis and timely pathogenetic therapy, the prognosis of the course of LAL-D, the duration and quality of life of the child were considered to be favourable.Raising the awareness of doctors along with the introduction of effective screening programs for the timely detection of dyslipidemia in children contributes to timely diagnosis and early initiation of pathogenetic therapy, which can increase the life expectancy of patients with lysosomal acid lipase deficiency and improve their quality of life.

Bicyclol Alleviates Atherosclerosis by Manipulating Gut Microbiota (Small 9/2022)

Atherosclerosis Treatment Herb derived drugs modulate gut microbiome homeostasis and gut-generated bio-metabolites. In article number 2105021, Jian-Dong Jiang, Yongsheng Che, Lu-Lu Wang, and co-workers modify the immune cell dynamics and liver function using herb-derived bicyclol, leading to improved chronic inflammation and cholesterol metabolism. The endothelial activation and cholesterol ester accumulation in the aortic arch are ameliorated causing less plaque onset.

Bicyclol Alleviates Atherosclerosis by Manipulating Gut Microbiota.

Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb-derived bicyclol (BIC) is a versatile bioactive compound that can be used to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(-/-) mice. Metagenome-wide association study analysis verifies that the modulation on carbohydrate-active enzymes and short-chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.

A case of mesenteric panniculitis in a patient with Tangier disease

Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.

Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue.

The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK–SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.