PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation

The role of the endoplasmic reticulum stress-regulated kinase, PERK, in mammary gland function was assessed through generation of a targeted deletion in mammary epithelium. Characterization revealed that PERK is required for functional maturation of milk-secreting mammary epithelial cells. PERK-dependent signaling contributes to lipogenic differentiation in mammary epithelium, and perk deletion inhibits the sustained expression of lipogenic enzymes FAS, ACL, and SCD1. As a result, mammary tissue has reduced lipid content and the milk produced has altered lipid composition, resulting in attenuated pup growth. Consistent with PERK-dependent regulation of the lipogenic pathway, loss of PERK inhibits expression of FAS, ACL, and SCD1 in immortalized murine embryonic fibroblasts when cultured under conditions favoring adipocyte differentiation. These findings implicate PERK as a physiologically relevant regulator of the lipogenic pathway.     

Discovery of analogues of non-β 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 aimsCholesterol 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 resultsPrimary 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.ConclusionsTaken 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.     

Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila

The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemia-related heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and lipid-induced cardiomyopathy. In the present study, we report that the Drosophila easily shocked (eas) mutants that harbor a disturbance in phosphatidylethanolamine (PE) synthesis display tachycardia and defects in cardiac relaxation and are prone to developing cardiac arrest and fibrillation under stress. The eas mutant hearts exhibit elevated concentrations of triglycerides, suggestive of a metabolic, diabetic-like heart phenotype. Moreover, the low PE levels in eas flies mimic the effects of cholesterol deficiency in vertebrates by stimulating the Drosophila sterol regulatory element-binding protein (dSREBP) pathway. Significantly, cardiac-specific elevation of dSREBP signaling adversely affects heart function, reflecting the cardiac eas phenotype, whereas suppressing dSREBP or lipogenic target gene function in eas hearts rescues the cardiac hyperlipidemia and heart function disorders. These findings suggest that dysregulated phospholipid signaling that alters SREBP activity contributes to the progression of impaired heart function in flies and identifies a potential link to lipotoxic cardiac diseases in humans.     

Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes

Acne vulgaris is a prevalent cutaneous disease characterized by a multifactorial pathogenic process including hyperseborrhea, inflammation, over‐keratinization of follicular keratinocytes and Propionibacterium acnes (P acnes) overgrowth. Salicylic acid (SA), a beta‐hydroxy acid, is frequently used in the treatment of acne. SA has been found to decrease skin lipids and to possess anti‐inflammatory properties. However, few studies have elucidated the mechanisms and pathways involved in such treatment of acne. In this study, we initially investigated the anti‐acne properties of SA in human SEB‐1 sebocytes. Treatment with SA decreased sebocyte lipogenesis by downregulating the adenosine monophosphate‐activated protein kinase (AMPK)/sterol response element‐binding protein‐1 (SREBP‐1) pathway and reduced inflammation by suppressing the NF‐κB pathway in these cells. Salicylic acid also decreased the cell viability of SEB‐1 by increasing apoptosis via the death signal receptor pathway. Subsequently, histopathological analysis of a rabbit ear acne model after application of SA for three weeks confirmed that SA suppressed the levels of cytokines and major pathogenic proteins around acne lesions, which supports the mechanisms suggested by our in vitro experiments. These results initially clarified that therapeutic activities of SA in acne vulgaris treatment could be associated with the regulation of SREBP‐1 pathway and NF‐κB pathway in human SEB‐1 sebocytes.     

Hepatic effects of a methionine-choline-deficient diet in hepatocyte RXRα-null mice

Retinoid X receptor-α (RXRα) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRα deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRα-null (H-RXRα-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid β-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRα-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRα-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRα-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRα-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRα-null mice. In conclusion, these data suggest a critical role for RXRα in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury.     

缺血性心脑血管疾病患者SCAP基因Ile796Val多态性的研究

目的　探讨甾醇调节因子结合蛋白裂解激活蛋白 (SCAP)基因 Ile796Val多态性与缺血性心脑血管疾病患者的相关性。方法　选取冠心病患者 1 1 2例分为 2组〔血清胆固醇 (TC)与甘油三酯 (TG)正常组 50例 ,血清 TC与 TG增高组 62例〕,缺血性脑卒中患者 53例。采用 PCR-RFLP的分析方法 ,检测老年人群中缺血性心脑血管疾病患者 SCAP基因 Ile796Val的多态性。结果　冠心病血脂正常组与对照组相比 ,基因型和等位基因差异无显著性 (P>0 .0 5)。冠心病血脂增高组和缺血性脑卒中组与对照组相比 ,基因型和等位基因均有显著性差异 (P<0 .0 5) ,且 A等位基因频率显著高于对照组。结论　 SCAP基因 Ile796Val多态性对心脑血管的遗传学研究具有重要意义。提示 SCAP基因 A等位基因与动脉粥样硬化有着密切的关系 ,并且增加了罹患缺血性心脑血管疾病的风险性。     

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”.     

鸡骨草总黄酮碳苷对乙硫氨酸导致的小鼠脂肪肝的影响简

目的：研究鸡骨草总黄酮碳苷（AME）对乙硫氨酸（DL-E）所致小鼠脂肪肝的影响,并探讨其作用机制。方法：ICR小鼠随机分为4组：对照组,DL-E造模组,AME组和AME＋DL-E组,每组8只。用AME连续灌胃给予AME组和AME＋DL-E组小鼠7d,另外两组给予溶剂对照（三蒸水）,第7天灌胃给予DL-E组和AME＋DL-E组250mg／kgDL-E造模,其他两组给予溶剂对照（0．2％CMC-Na）。造模1h后再次灌胃给予所有小鼠AME或溶剂对照（三蒸水）,造模22h后收集血样和肝组织,采用生化法测定血清脂质和转氨酶水平,肝脏TG以及TC含量。采用实时定量PCR的方法测定肝脏中相关脂代谢基因水平。结果：AME可以显著减少小鼠肝脏脂肪空泡的数量和脂变的面积,降低TG和TC含量以及血清转氨酶水平。在脂质相关代谢基因的调控上,AME可以下调DL-E导致的固醇调节元件结合蛋白-1（Sterolregulatoryelementbind-ingprotein1,SREBP-1）、脂肪酸合成酶（Fattyacidsynthase,FAS）和乙酰辅酶A羧化酶（Aee-tyl-CoAcarboxylase1,ACCl）的高表达,并且AME可以逆转DL-E对过氧化物酶体增殖物活化受体α（Peroxisomeproliferatoractivativedre-ceptora,PPARα）和肉碱棕榈酰转移酶1α（Carnitinepalmitoyltransferase1α,CPT-1α）的抑制作用。结论：AME对DL-E引起的小鼠肝脏脂肪蓄积具有保护作用,并且这种作用主要是通过减少脂质合成,促进脂质氧化代谢来实现的。