Lipid metabolism within the bone micro-environment is closely associated with bone metabolism in physiological and pathophysiological stages

Recent advances in society have resulted in the emergence of both hyperlipidemia and obesity as life-threatening conditions in people with implications for various types of diseases, such as cardiovascular diseases and cancer. This is further complicated by a global rise in the aging population, especially menopausal women, who mostly suffer from overweight and bone loss simultaneously. Interestingly, clinical observations in these women suggest that osteoarthritis may be linked to a higher body mass index (BMI), which has led many to believe that there may be some degree of bone dysfunction associated with conditions such as obesity. It is also common practice in many outpatient settings to encourage patients to control their BMI and lose weight in an attempt to mitigate mechanical stress and thus reduce bone pain and joint dysfunction. Together, studies show that bone is not only a mechanical organ but also a critical component of metabolism, and various endocrine functions, such as calcium metabolism. Numerous studies have demonstrated a relationship between metabolic dysfunction in bone and abnormal lipid metabolism. Previous studies have also regarded obesity as a metabolic disorder. However, the relationship between lipid metabolism and bone metabolism has not been fully elucidated. In this narrative review, the data describing the close relationship between bone and lipid metabolism was summarized and the impact on both the normal physiology and pathophysiology of these tissues was discussed at both the molecular and cellular levels.

Ferroptosis Signaling and Regulators in Atherosclerosis

Atherosclerosis (AS) is a major cause of cardiovascular diseases such as coronary heart disease, heart failure and stroke. Abnormal lipid metabolism, oxidative stress and inflammation are the main features of AS. Ferroptosis is an iron-driven programmed cell death characterized by lipid peroxidation, which have been proved to participate in the development and progression of AS by different signal pathways. NRF2-Keap1 pathway decreases ferroptosis associated with AS by maintaining cellular iron homeostasis, increasing the production glutathione, GPX4 and NADPH. The p53 plays different roles in ferroptosis at different stages of AS in a transcription-dependent and transcription- independent manner. The Hippo pathway is involved in progression of AS, which has been proved the activation of ferroptosis. Other transcription factors, such as ATF3, ATF4, STAT3, also involved in the occurrence of ferroptosis and AS. Certain proteins or enzymes also have a regulatory role in AS and ferroptosis. In this paper, we review the mechanism of ferroptosis and its important role in AS in an attempt to find a new relationship between ferroptosis and AS and provide new ideas for the future treatment of AS.

Frequency of Dyslipidemia in patients with Psoriasis and Association with Disease Severity

Background: Psoriasis is a recurrent disfiguring skin disease, associated with abnormal lipid metabolism and with high occurrence of cardiovascular complications. This linked to the extent of disease, as it is often seen in those patients who have larger body areas involved with psoriasis. Objective: To estimate frequency of dyslipidemia in psoriatic patients and to determine the frequency of dyslipidemia in psoriatic patients based on the severity of disease. Study Design: Cross-sectional study Place and Duration of Study: Department of Dermatology, Fauji Foundation Hospital Rawalpindi from 1stMarch 2017 to 30th September 2017. Methodology: One hundred and fifty cases were enrolled. All cases were enrolled and 3ml of blood was collected following 12 hrs of fasting for determination of lipid profile. Blood sample was sent to the Hospital laboratory and reports were verified by senior pathologists. Severity of psoriasis was determined according to PASI score. Results: Age of participants was between 18-60 years with mean 38.88±12.26 years and 29 (19.33%) male and 121 (80.67%) female cases. According to severity of disease, 50 (33.3%) cases had mild, 70 (46.7%) had moderate and 30(20%) cases had severe Psoriasis. The mean cholesterol, triglycerides (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) was 12.91 ± 2.17, 8.93 ± 2.90, 5.0 ± 2.28 and 1.98 ± 0.31 respectively. There were 100(66.7%) cases who had dyslipidemia and 50(33.3%) had normal lipid profile. Conclusion: Frequency of dyslipidemia is very high and is associated with severity of psoriasis. Keywords: Psoriasis, Dyslipidemia, Lipid profile and Cardiovascular disease.

Novel Oncogenic Non-Coding RNA：circRIC8B Regulates Lipid Metabolism Via Mir-199b-5p /LPL Axis in Chronic Lymphocytic Leukemia

Objective: During tumor development, energy constraints caused by malnourished microenvironments could exert selective pressure on cancer cells. Tumor cells are driven to metabolic reprogramming to meet the increased demand for energy and metabolites for their rapid proliferation and survival. Chronic lymphocytic leukemia (CLL) is a disease with about 1% of CLL cells proliferating every day which is highly than commonly thought. CLL cells were reported to maintain high levels of proliferation through metabolic changes, but extensive studies did not clearly explain the underlying mechanism of driving genes in CLL metabolism. Circular RNA (circRNA) has recently been shown to play an important role in cell metabolism through lipid accumulation. The purpose of this study is to explore the role of circRNA in lipid metabolism of CLL and provide novel therapeutic targets for CLL. Methods: To analyze circRNAs expression profiles and metabolism map in CLL, peripheral blood mononuclear cells (PBMC) from 53 treatment-naïve CLL patients were collected for transcriptome sequencing. Candidate circRNA circRIC8B in a larger cohort of patients was validated and the clinical characteristics were analyzed. Overexpression and knockdown virus were constructed to infect CLL cells, and untargeted metabolomics was used to find the key lipid metabolic pathway modulating by circRIC8B. The oncogenic functions of circRIC8B were further measured in CLL cell lines (MEC-1 and JVM-3) by performing CCK8 assay, flow cytometry, nile red staining and triglyceride detection. Moreover, we explored the molecular mechanisms of circRIC8B and verified the interactions among circRIC8B, miR-199b-5p and LPL by performing RNA-FISH, RIP, dual-luciferase reporter assay and Western blotting. The killing effects of lipid metabolism inhibitors on CLL cells were detected by CCK8 and flow cytometry. Results Transcriptome analysis showed that abnormal lipid metabolism was significantly related to the survival and prognosis of patients with CLL, and circRNAs could be involved in the regulation of lipid metabolism. Kaplan-Meier survival analysis confirmed that patients with higher fatty acid biosynthesis had a significantly lower OS (Figure 1A-B). circRIC8B which is positively correlated with the expression of lipoprotein lipase (LPL) was finally selected for further investigation. qRT-PCR analysis showed that circRIC8B was significantly higher expressed in CLL compared with healthy donors. Moreover, consistent with the sequencing results, circRIC8B was positively correlated with LPL and highly relevant to IGHV region mutation status, which has long been considered as an important prognostic indicator of CLL (Figure 1C). Patients with higher circRIC8B level are associated with worse survival and advanced disease progression (Figure 1D and E). LC-MS/MS results showed that circRIC8B are able to modulated lipid metabolism of CLL cells. Functional analysis demonstrated the promoting role of circRIC8B in cell proliferation. Nile red staining showed lipid accumulation in CLL cells with circRIC8B overexpression increased significantly, while lipid accumulation in circRIC8B knockdown cells decreased significantly, and the quantitative results of triglycerides were similar. Next, we unraveled an original mechanism in CLL that up-regulated circRIC8B was mainly enriched in the cytoplasm, acted as a "sponge" of miR-199b-5p. CCK8 assay, nile red staining showed that the cell viability and lipid accumulating of CLL cell lines were evidently decreased after RNAi of circRIC8B and this result could be reversed by miR-199b-5p inhibitor transfection (Figure 1F-H). In addition, ezetimibe, one of the inhibitors of lipid metabolism was found effectively inhibit the proliferation and promote apoptosis of CLL cells. Conclusions In conclusion, as an independent prognostic factor of CLL, circRIC8B was involved in the progress of CLL disease through the miR-199b-5p/LPL axis. In addition, circRIC8B is a key factor in regulating lipid accumulation in CLL, resulting in significant changes in cellular lipid storage, thus supporting the proliferation of CLL cells. Metabolic inhibitor Ezetimibe can effectively block this process and exert anti-tumor functions. This study provides new clues for the role of circRNA in abnormal lipid metabolism of CLL and novel therapeutic strategy for CLL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Influence of Dietary Behaviors on Dyslipidemia in Pregnant Women and Its Effects on Physical Development of Fetuses and Infants: A Bidirectional Cohort Study

Background: Gestational diabetes can alter the trajectory of fetal development, but there are few studies on the effects of abnormal lipid metabolism on physical development of infants. We aimed to explore the prevalence of maternal dyslipidemia, its influencing factors and effects on the physical development of fetuses and infants, as well as the role of leptin in this process. Methods: Questionnaire surveys and main outcome measures were administered among 338 pairs of pregnant women and newborns. Results: The detection rate of maternal dyslipidemia was 31.5%. The median levels of TG (triglyceride) and TG/HDL (high-density lipoprotein) ratio were higher in large-for-gestational-age (LGA) newborns. Birth weight was positively related to infants’ height and weight at six months and one year old (p < 0.05). Leptin was positively related to TG levels of pregnant women and newborns’ birth weight (p < 0.05). Logistic regression analysis showed that having greater than or equal to four meals a day (OR = 6.552, 95%CI = 1.014–42.338) and liking to eat lightly flavored food during pregnancy (OR = 1.887, 95%CI = 1.048–3.395) were independent risk factors of maternal dyslipidemia. Conclusions: The prevalence of dyslipidemia was relatively high in pregnant women and was affected by dietary behaviors. Abnormal lipid levels during pregnancy could affect weight and length at birth, which might be associated with increasing leptin levels in cord blood, and then the weight of infants would be influenced by birth weight.

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy

Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.

Risk factors of cerebral microbleeds in young and middle-aged patients with hypertension

Background & Objectives: This study aimed to explore the incidence and potential risk factors of cerebral microbleeds (CMBs) in young and middle-aged patients with hypertension. Methods: We retrospectively analyzed the clinical data of young and middle-aged patients with hypertension in the Department of Neurology, General Hospital of Western Theater Command, Chengdu, China between August 2018 and December 2020. The demographic baseline, laboratory parameters and clinical imaging data were collected. Microbleed anatomical rating scale (MARS) was applied to evaluate the presence, amount, and topographical distributions of CMBs. Results: Among 196 young and middle-aged patients with hypertension, 84 (42.9%) patients had CMBs. CMBs were more likely to occur in the deep brain tissue regions (41.8%), followed by lobar or infratentorial region. White matter hyperintensity (OR, 5.262; 95%CI, 1.314-21.075; P=0.019), abnormal lipid metabolism (OR, 3.832; 95%CI, 1.578-9.306; P=0.003), usage of anti-platelet aggregation drugs (OR, 2.947; 95%CI, 1.138-7.632; P=0.026), smoking history (OR, 3.218; 95%CI, 1.073-9.651; P=0.037), and hyperhomocysteinemia (OR, 1.415; 95%CI, 1.018-1.967; P=0.039) were independently associated with deep or infratentorial CMBs in young and middle-aged patients with hypertension. However, the occurrence of strictly lobar CMBs was only independently associated with abnormal lipid metabolism (OR, 4.162; 95%CI, 1.685-10.282; P=0.002). Conclusions: The rate of CMBs was high in young and middle-aged patients with hypertension, most commonly occurring in the deep brain tissue region. While multiple risk factors were identified to be associated with deep or infratentorial CMBs, the occurrence of strictly lobar CMBs was only associated with abnormal lipid metabolism.