SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes.

Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington's disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element-binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP2-controlled genes in the cholesterol biosynthesis pathway. Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the transcriptionally active N-terminal fragment of human SREBP2 (hSREBP2). Robust hSREBP2 expression in striatal glial cells in R6/2 Huntington's disease mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed dopamine receptor D2 (Drd2) transcript levels decline, cleared mutant huntingtin aggregates and attenuated behavioural deficits. We conclude that glial SREBP2 participates in Huntington's disease brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of the disease.

Expression of SREBP2 and cholesterol metabolism related genes in TCGA glioma cohorts.

Diffuse gliomas are the most common primary brain tumors. The Cancer Genome Atlas (TCGA) database provides correlative evidence between altered molecular pathways and gliomas. Dysregulated cholesterol homeostasis emerges as a potential indicator of the pathogenesis of gliomas.Mining large cohorts from the TCGA together with database from the Chinese Glioma Genome Atlas (CGGA) for confirmation, we compared gene expression of cholesterol synthesis master regulator SREBP2 and its regulatory networks in low grade glioma (LGG) and glioblastoma (GBM).Our analysis shows that expression of SREBP2 and related genes is lower in GBM than in LGG, indicating that cholesterol metabolism processes, including de novo synthesis, cholesterol uptakes, and cholesterol conversion and efflux, are suppressed in GBM.Overall, our data suggests that SREBP2 transcript could serve as a potential prognosis marker or therapeutic target in diffuse glioma including GBM.

SREBP2 is upregulated in esophageal squamous cell carcinoma and co­operates with c­Myc to regulate HMGCR expression.

Dysregulations of the mevalonate pathway (MVA) have been previously identified. Our previous study demonstrated that 3­hydroxy­3­methylglutaryl­coenzyme A reductase (HMGCR), the rate­limiting enzyme of the MVA pathway, was upregulated in esophageal squamous cell carcinoma (ESCC) and statin­inhibited ESCC tumorigenesis. However, the underlying mechanism of HMGCR regulation in ESCC remains unknown. In the present study, western blotting and immunohistochemistry analysis demonstrated that sterol regulatory element­binding protein 2 (SREBP2), the master regulator for HMGCR, was upregulated in ESCC clinical samples. Overexpression of SREBP2 expression in ESCC cell lines promoted the growth, migration and colony formation of cancer cells in the MTT, Boyden chamber and soft agar assays, respectively, which was inhibited by lovastatin. Downregulation of SREBP2 expression in ESCC cell lines inhibited the viability, and migration and colony formation abilities of cancer cells. Assessment of the molecular mechanism demonstrated that SREBP2 interacted with c­Myc and cooperated with c­Myc to activate HMGCR expression. Collectively, the present study identified SREBP2 as an oncogene associated with the tumorigenesis of ESCC and further demonstrated the therapeutic effects of statins in ESCC.

Effects of SIRT1 gene knock-out via activation of SREBP2 protein-mediated PI3K/AKT signaling on osteoarthritis in mice.

This study investigated the effects of SIRT1 gene knock-out on osteoarthritis in mice, and the possible roles of SREBP2 protein and the PI3K/AKT signaling pathway in the effects. Mice were randomly divided into a normal group and a SIRT1 gene knock-out group (6 mice in each group). In these groups, one side of the knee anterior cruciate ligament was traversed, and the ipsilateral medial meniscus was cut to establish an osteoarthritis model of knee joint. The countralateral synovial bursa was cut out, serving as controls. The knee joint specimens were then divided into four groups: SIRT1+/+ control group (group A, n=6); SIRT1+/+ osteoarthritis group (group B, n=6); SIRT1-/- control group (group C, n=6); SIRT1-/- osteoarthritis group (group D, n=6). HE staining, Masson staining, Safranin O-Fast Green staining and Van Gieson staining were used to observe the morphological changes in the articular cartilage of the knee. Immunohistochemical staining was employed to detect the expression of SIRT1, SREBP2, VEGF, AKT, HMGCR and type II collagen proteins. SA-ß-gal staining was utilized to evaluate chondrocyte aging. The results showed clear knee joint cartilage destruction and degeneration in the SIRT1-/- osteoarthritis group. The tidal line was twisted and displaced anteriorly. Type II collagen was destroyed and distributed unevenly. Compared with the SIRT1+/+ osteoarthritis group and SIRT1-/- control group, SIRT1 protein expression was not obviously changed in the SIRT1-/- osteoarthritis group (P>0.05), while the expression levels of the SREBP2, VEGF and HMGCR proteins were significantly increased (P<0.05) and the levels of AKT and type II collagen proteins were significantly decreased (P<0.05). SIRT1 gene knock-out may aggravate cartilage degeneration in osteoarthritis by activating the SREBP2 protein-mediated PI3K/AKT signalling pathway, suggesting that SIRT1 gene may play a protective role against osteoarthritis.

Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.

The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments.

Naringin regulates cholesterol homeostasis and inhibits inflammation via modulating NF-κB and ERK signaling pathways in vitro.

The main purpose of this study was to examine if naringin contributed to the regulation of cholesterol homeostasis and inflammatory cytokine expressions in cholesterol and 25-OH-cholesterol-treated HepG2 cells and TNF-α-treated HUVECs. The gene and protein expressions related to cholesterol homeostasis and inflammation were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. We obtained the following results: (1) A concentration-dependent increase of LDLR and CYP7A1 expressions was observed, through activating expressions of SREBP2 and PPARy in HepG2 cells after exposure to naringin; (2) EL gene and protein expressions in HUVECs were inhibited by naringin; (3) the expressions of inflammatory factors such as CRP, TNF-α, ICAM-1 and VCAM-1 in HepG2 cells, ICAM-1 and VCAM-1 in HUVECs restrained by naringin were confirmed; (4) NF-κB and ERK1/2 activities were quenched by naringin. In summary, naringin might not only effectively reduce cholesterol levels by stimulating cholesterol metabolism but also inhibit inflammatory response through reducing inflammatory cytokine expressions. The effects of naringin were achieved via modulating NF-κB and ERK signaling pathways.

The Flavone Luteolin Suppresses SREBP-2 Expression and Post-Translational Activation in Hepatic Cells.

High blood cholesterol has been associated with cardiovascular diseases. The enzyme HMG CoA reductase (HMGCR) is responsible for cholesterol synthesis, and inhibitors of this enzyme (statins) have been used clinically to control blood cholesterol. Sterol regulatory element binding protein (SREBP) -2 is a key transcription factor in cholesterol metabolism, and HMGCR is a target gene of SREBP-2. Attenuating SREBP-2 activity could potentially minimize the expression of HMGCR. Luteolin is a flavone that is commonly detected in plant foods. In the present study, Luteolin suppressed the expression of SREBP-2 at concentrations as low as 1 µM in the hepatic cell lines WRL and HepG2. This flavone also prevented the nuclear translocation of SREBP-2. Post-translational processing of SREBP-2 protein was required for nuclear translocation. Luteolin partially blocked this activation route through increased AMP kinase (AMPK) activation. At the transcriptional level, the mRNA and protein expression of SREBP-2 were reduced through luteolin. A reporter gene assay also verified that the transcription of SREBF2 was weakened in response to this flavone. The reduced expression and protein processing of SREBP-2 resulted in decreased nuclear translocation. Thus, the transcription of HMGCR was also decreased after luteolin treatment. In summary, the results of the present study showed that luteolin modulates HMGCR transcription by decreasing the expression and nuclear translocation of SREBP-2.

Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. METHODS AND RESULTS: The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2. CONCLUSIONS: FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.

Matrix metalloproteinase-2 mediates a mechanism of metabolic cardioprotection consisting of negative regulation of the sterol regulatory element-binding protein-2/3-hydroxy-3-methylglutaryl-CoA reductase pathway in the heart.

Previously, we reported that cardiac matrix metalloproteinase (MMP)-2 is upregulated in hypertensive mice. How MMP-2 affects the development of cardiac disease is unclear. Here, we report that MMP-2 protects from hypertensive cardiac disease. In mice infused with angiotensin II, the lack of MMP-2 (Mmp2(-/-)) did not affect the severity of the hypertension but caused cardiac hypertrophy to develop earlier and to a greater extent versus wild-type (Mmp2(+/+)) mice, as measured by heart weight:body weight ratio and upregulation of hypertrophy and fibrosis markers. We further found numerous metabolic and inflammatory gene expression abnormalities in the left ventricle of Mmp2(-/-) mice. Interestingly, Mmp2(-/-) mice expressed greater amounts of sterol regulatory element-binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (a target of sterol regulatory element-binding protein-2-mediated transcription and rate limiting enzyme in cholesterol and isoprenoids biosynthesis) in addition to markers of inflammation including chemokines of the C-C motif ligand family. We focused on the functionally related genes for sterol regulatory binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, lovastatin, attenuated angiotensin II-induced cardiac hypertrophy and fibrosis in Mmp2(-/-) and wild-type (Mmp2(+/+)) mice, with Mmp2(-/-) mice showing resistance to cardioprotection by lovastatin. MMP-2 deficiency predisposes to cardiac dysfunction as well as metabolic and inflammatory gene expression dysregulation. This complex phenotype is, at least in part, because of the cardiac sterol regulatory element-binding protein-2/3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway being upregulated in MMP-2 deficiency.

Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1.

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.

Endothelial dysfunction: the role of sterol regulatory element-binding protein-induced NOD-like receptor family pyrin domain-containing protein 3 inflammasome in atherosclerosis.

PURPOSE OF REVIEW: Great effort has been devoted to elucidate the molecular mechanisms by which inflammasome in macrophages contributes to atherosclerosis. Inflammasome in vascular endothelial cells and its causal relationship with endothelial dysfunction in atherosclerosis are less understood. Here, we review the recent studies of inflammasome and its activation in endothelial cells, and highlight such endothelial inflammatory response in atherosclerosis. RECENT FINDINGS: Inflammasomes are critical effectors in innate immunity, and their activation in macrophages and the arterial wall contributes to atherogenesis. Sterol regulatory element-binding protein 2, a master regulator in cholesterol biosynthesis, can be activated in a noncanonical manner, which leads to the activation of the NOD-like receptor family pyrin domain-containing protein inflammasome in macrophages and endothelial cells. Results from in-vitro and in-vivo models suggest that sterol regulatory element-binding protein 2 is a key molecule in aggravating proinflammatory responses in endothelial cells and promoting atherosclerosis. SUMMARY: The SREBP-induced NOD-like receptor family pyrin domain-containing protein inflammasome and its instigation of innate immunity is an important contributor to atherosclerosis. Elucidating the underlying mechanisms will expand our understanding of endothelial dysfunction and its dynamic interaction with vascular inflammation. Furthermore, targeting SREBP-inflammasome pathways can be a therapeutic strategy for attenuating atherosclerosis.

Molecular and functional characterization of LRP1 promoter polymorphism c.1-25 C>G (rs138854007).

The transcription of the Low-density lipoprotein receptor-related protein (LRP1) is upregulated by aggregated LDL (agLDL) and angiotensin II (AngII) in human vascular smooth muscle cells (hVSMC). The polymorphism c.1-25C>G creates a new GC-box in the LRP1 promoter recognized by Sp1/Sp3 transcription factors. The aims of this study were 1) to evaluate the impact of c.1-25C>G polymorphism on LRP1 transcriptional activity and expression, and 2) to examine the response of c.1-25C>G LRP1 promoter to LDL and AngII. EMSA and Luciferase assays in HeLa cells showed that -25G promoter has enhanced basal transcriptional activity and specific Sp1/Sp3 binding. hVSMC with GG genotype (GG-hVSMC) had higher LRP1 mRNA and protein levels, respectively than CC genotype (CC-hVSMC). EMSA assays showed that the polymorphism determines scarce amount of SRE-B/SREBP-2 complex formation and the failure of agLDL to further reduce these SRE-B/SREBP-2 complexes. Taken together, these results suggest that c.1-25C>G, by difficulting SREBP-2 binding, prevents SREBP-2 displacement required for LRP1 promoter response to LDL. In contrast, c.1-25C>G strongly favours Sp1/Sp3 binding and AngII-induced activity in Sp1/Sp3 dependent manner in GG-hVSMC. This increase is functionally translated into a higher capacity of GG-hVSMC to become foam cells from agLDL in presence of AngII. These results suggest that c.1-25C>G determines a lack of response to agLDL and an exacerbated response to AngII. It is thus conceivable that the presence of the polymorphism would be easily translated to vascular alterations in the presence of the pro-hypertensive autacoid, AngII.

Interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis.

BACKGROUND: The activation of the renin-angiotensin system (RAS) and lipid disorders are major risk factors in progressive chronic kidney disease. This study aimed to investigate the potential synergistic mechanisms of RAS activation and lipid disorders that contribute to glomerulosclerosis. MATERIALS AND METHODS: Human renal mesangial cells (HMCs) were treated with 10(-7) mol/L angiotensin II (Ang II) or with 30 µg/ml cholesterol and 1 µg/ml 25-hydroxycholesterol (lipid loading) for 24 hours. Lipid accumulation in the cells was evaluated by Oil Red O staining and intracellular cholesterol quantitative assays. The gene and protein expression of molecules in the low-density lipoprotein receptor (LDLr) pathway, the RAS family, and the extracellular matrix were examined by real-time polymerase chain reaction and Western blotting. The translocation of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), which escorts SREBP-2 from the endoplasmic reticulum (ER) to the Golgi, was examined by immunofluorescent staining. RESULTS: Ang II increased lipid droplet accumulation in HMCs. Further analysis revealed that Ang II increased the mRNA and protein expression of LDLr, SCAP, and SREBP-2. This increase was correlated with an enhanced translocation of the SCAP/SREBP-2 complex from the ER to the Golgi in HMCs that was induced by Ang II, thereby activating LDLr gene transcription. Interestingly, lipid loading increased the mRNA and protein expression of angiotensinogen, Ang II, renin, angiotensin-converting enzyme, angiotensin II type 1 receptor, and type 2 receptor in HMCs with increased mRNA and protein expression of collagen I, α-smooth muscle actin, and fibronectin. CONCLUSIONS: This study demonstrates that the interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis.

Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.

Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis.

High levels of dietary phytosterols affect lipid metabolism and increase liver and plasma TAG in Atlantic salmon (Salmo salar L.).

Replacing dietary fishmeal (FM) and fish oil (FO) with plant ingredients in Atlantic salmon (Salmo salar L.) diets decreases dietary cholesterol and introduces phytosterols. The aim of the present study was to assess the effect of dietary sterol composition on cholesterol metabolism in Atlantic salmon. For this purpose, two dietary trials were performed, in which Atlantic salmon were fed either 100 % FM and FO (FM-FO) diet or one of the three diets with either high (80 %) or medium (40 %) plant protein (PP) and a high (70 %) or medium (35 %) vegetable oil (VO) blend (trial 1); or 70 % PP with either 100 % FO or 80 % of the FO replaced with olive, rapeseed or soyabean oil (trial 2). Replacing ≥ 70 % of FM with PP and ≥ 70 % of FO with either a VO blend or rapeseed oil increased plasma and liver TAG concentrations. These diets contained high levels of phytosterols and low levels of cholesterol. Fish fed low-cholesterol diets, but with less phytosterols, exhibited an increased expression of genes encoding proteins involved in cholesterol uptake and synthesis. The expression of these genes was, however, partially inhibited in rapeseed oil-fed fish possibly due to the high dietary and tissue phytosterol:cholesterol ratio. Atlantic salmon tissue and plasma cholesterol concentrations were maintained stable independent of the dietary sterol content.

MicroRNA-33a mediates the regulation of high mobility group AT-hook 2 gene (HMGA2) by thyroid transcription factor 1 (TTF-1/NKX2-1).

In lung cancers, TTF-1 displays seemingly paradoxical activities. Although TTF-1 is amplified in primary human lung cancers, it inhibits primary lung tumors from metastasizing in a mouse model system. It was reported that the oncogenic proepithelial mesenchymal transition (EMT) high mobility group AT-hook 2 gene (HMGA2) mediates the antimetastatic function of TTF-1. To gain mechanistic insight into the metastasis-critical signaling axis of TTF-1 to HMGA2, we used both reverse and forward strategies and discovered that microRNA-33a (miR-33a) is under direct positive regulation of TTF-1. By chromatin immunoprecipitation, we determined that TTF-1 binds to the promoter of SREBF2, the host gene of miR-33a. The 3'-untranslated region (UTR) of HMGA2 contains three predicted binding sites of miR-33a. We showed that the first two highly conserved sites are conducive to HMGA2 repression by miR-33a, establishing HMGA2 as a genuine target of miR-33a. Functional studies revealed that enforced expression of miR-33a inhibits the motility of lung cancer cells, and this inhibition can be rescued by overexpression of the form of HMGA2 without the 3'-UTR, suggesting that TTF-1 keeps the prometastasis gene HMGA2 in check via up-regulating miR-33a. This study reports the first miRNAs directly regulated by TTF-1 and clarifies how TTF-1 controls HMGA2 expression. Moreover, the documented importance of SREBF2 and miR-33a in regulating cholesterol metabolism suggests that TTF-1 may be a modulator of cholesterol homeostasis in the lung. Future studies will be dedicated to understanding how miRNAs influence the oncogenic activity of TTF-1 and the role of TTF-1 in cholesterol metabolism.

Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia.

The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)-apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)-apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67-84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.

Proinflammatory gene expression and renal lipogenesis are modulated by dietary protein content in obese Zucker fa/fa rats.

Obesity is a risk factor for the development of chronic kidney disease (CKD) and end-stage renal disease. It is not clear whether the adoption of a high-protein diet in obese patients affects renal lipid metabolism or kidney function. Thus the aims of this study were to assess in obese Zuckerfa/fa rats the effects of different types and amounts of dietary protein on the expression of lipogenic and inflammatory genes, as well as renal lipid concentration and biochemical parameters of kidney function. Rats were fed different concentrations of soy protein or casein (20, 30, 45%) for 2 mo. Independent of the type of protein ingested, higher dietary protein intake led to higher serum triglycerides (TG) than rats fed adequate concentrations of protein. Additionally, the soy protein diet significantly increased serum TG compared with the casein diet. However, rats fed soy protein had significantly decreased serum cholesterol concentrations compared with those fed a casein diet. No significant differences in renal TG and cholesterol concentrations were observed between rats fed with either protein diets. Renal expression of sterol-regulatory element binding protein 2 (SREBP-2) and its target gene HMG-CoA reductase was significantly increased as the concentration of dietary protein increased. The highest protein diets were associated with greater expression of proinflammatory cytokines in the kidney, independent of the type of dietary protein. These results indicate that high soy or casein protein diets upregulate the expression of lipogenic and proinflammatory genes in the kidney.

Decreased NPC1L1 expression in the liver from Chinese female gallstone patients.

BACKGROUND: Cholesterol gallstone disease is a very common disease in both industrialized and developing countries. Many studies have found that cholesterol gallstones are more common in women than men. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans. AIMS: The aim of this study is to probe for underlying hepatic molecular defects associated with development of gallstones in female. METHODS/RESULTS: Fifty-seven nonobese, normolipidemic Chinese female gallstone patients (GS) were investigated with 12 age- and body mass index-matched female gallstone-free controls (GSF). The bile from the female GS had higher cholesterol saturation than that from the female GSF. The hepatic NPC1L1 mRNA levels were lower in female GS, correlated with SREBP2 mRNA. NPC1L1 downregulation was confirmed at protein levels. Consistently, immunohistochemistry showed decreased NPC1L1 expression in female GS. CONCLUSIONS: The decreased hepatic NPC1L1 levels in female GS might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile. Our data are consistent with the possibility that hepatic NPC1L1 may be mediated by SREBP2.