Microsomal Triglyceride Transfer Protein Expression Research Articles

ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet-Fed ApoE-/- Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux.

Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered Asgr1 knockout mice (Asgr1-/-), Asgr1 and ApoE double-knockout mice (Asgr1-/-ApoE-/-), and ASGR1-overexpressing mice on an ApoE-/- background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. After being fed a Western diet for 12 weeks, Asgr1-/-ApoE-/- mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE-/- mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE-/- mice. In addition, ASGR1 deficiency exacerbated liver injury in Western diet-induced Asgr1-/-ApoE-/- mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced Asgr1-/- mice, while its overexpression mitigated liver injury in Western diet-induced ASGR1-overexpressing ApoE-/- mice. Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed ApoE-/- mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.

Rice Protein Reduces Triglyceride Levels through Modulating CD36, MTP, FATP, and FABP Expression in Growing and Adult Rats.

To elucidate the effect of rice protein on the regulation of triglyceride transport to reduce triglyceride levels, growing and adult male Wistar rats were fed with casein and rice protein for 2 weeks. With the intake of rice protein, the gene and protein expressions of cluster determinant 36 (CD36), microsomal triglyceride transfer protein (MTP), fatty acid transport protein-2 (FATP-2), and fatty acid-binding protein-1 (FABP-1) were, respectively, downregulated in growing and adult rats, suggesting rice protein could effectively regulate triglyceride transport. As a result, rice protein significantly reduced plasma levels of triglyceride and fatty acids, while hepatic accumulations of triglyceride and fatty acids were also decreased via rice protein. The present study demonstrates that RP exerts regulatory effects on CD36, MTP, FATP-2, and FABP-1 expression in growing and adult rats, revealing a link to triglyceride-lowering actions and the modulations of triglyceride transport exerted by rice protein. Results suggest that the aging process cannot attenuate the depression of CD36, MTP, FATP, and FABP 19 expression to reduce triglyceride levels induced by rice protein.

Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine β-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation

Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine β-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.

Expression and prognostic significance of microsomal triglyceride transfer protein in brain tumors: a retrospective cohort study.

Glioblastoma (GBM) is the most common malignant brain tumor and has poor survival. An elevated cholesterol level is involved occurrence and progression of brain tumors. Microsomal triglyceride transfer protein (MTTP) is a target for lowering lipids, and its inhibition helps to improve hyperlipidemia. However, whether the altered expression of MTTP affects the development and prognosis of brain tumors is currently unidentified. The purpose of this study is to determine MTTP as a prognostic marker for brain tumors. Data for patients with brain cancers and control brain tissue were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The datasets were analyzed using Mann-Whitney U-test or t-test to compare the expression of MTTP in normal and brain tumor tissues. To examine whether MTTP affected the prognosis of patients with brain tumors, log-rank test and multivariable Cox proportional hazard regression were conducted. The expression of MTTP was significantly upregulated in brain tumors and was correlated with age, tumor stage, and isocitrate dehydrogenase (IDH) mutation. Importantly, increased MTTP expression in brain tumors is associated with poor patient survival. High MTTP expression is associated with brain tumor development, tumor stage, and prognosis. Therefore, MTTP is an independent prognostic indicator for brain tumors, which can serve as one of the possible targets for adjuvant treatment of GBM.

Nuclear lipid droplets in Caco2 cells originate from nascent precursors and in situ at the nuclear envelope

Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid droplets (nLDs) are present in intestinal cells but their origin and relationship to cytoplasmic TAG synthesis and secretion is unknown. nLDs and related lipid-associated promyelocytic leukemia structures (LAPS) were abundant in oleate-treated Caco2 but less frequent in other human colorectal cancer cell lines and mouse intestinal organoids. nLDs and LAPS in undifferentiated oleate-treated Caco2 cells harbored the phosphatidate phosphatase Lipin1, its product diacylglycerol, and CTP:phosphocholine cytidylyltransferase (CCT)α. CCTα knockout Caco2 cells had fewer but larger nLDs, indicating a reliance on de novo PC synthesis for assembly. Differentiation of Caco2 cells caused large nLDs and LAPS to form regardless of oleate treatment or CCTα expression. nLDs and LAPS in Caco2 cells did not associate with apoCIII and apoAI and formed dependently of microsomal triglyceride transfer protein expression and activity, indicating they are not derived from endoplasmic reticulum luminal LDs precursors. Instead, undifferentiated Caco2 cells harbored a constitutive pool of nLDs and LAPS in proximity to the nuclear envelope that expanded in size and number with oleate treatment. Inhibition of TAG synthesis did affect the number of nascent nLDs and LAPS but prevented their association with promyelocytic leukemia protein, Lipin1α, and diacylglycerol, which instead accumulated on the nuclear membranes. Thus, nLD and LAPS biogenesis in Caco2 cells is not linked to lipoprotein secretion but involves biogenesis and/or expansion of nascent nLDs by de novo lipid synthesis.

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion

ObjectivesThe assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion. MethodsPdia1/P4hb was conditionally deleted in adult mouse hepatocytes and the phenotypes characterized. Mechanistic analyses in primary hepatocytes determined how PDIA1 ablation alters MTTP synthesis and degradation as well as altering synthesis and secretion of Apolipoprotein B (APOB), along with complementary expression of intact PDIA1 vs a catalytically inactivated PDIA1 mutant. ResultsHepatocyte-specific deletion of Pdia1/P4hb inhibited hepatic MTTP expression and dramatically reduced VLDL production, leading to severe hepatic steatosis and hypolipidemia. Pdia1-deletion did not affect mRNA expression or protein stability of MTTP but rather prevented Mttp mRNA translation. We demonstrate an essential role for PDIA1 in MTTP synthesis and function and show that PDIA1 interacts with APOB in an MTTP-independent manner via its molecular chaperone function to support APOB folding and secretion. ConclusionsPDIA1 plays indispensable roles in APOB folding, MTTP synthesis and activity to support VLDL assembly. Thus, like APOB and MTTP, PDIA1 is an obligatory component of hepatic VLDL production.

Regulating microsomal triglyceride transfer protein with natural products for the treatment of hyperlipidaemia

Hyperlipidaemia, characterised by elevated levels of lipids, particularly LDL-C, is a significant risk factor for atherosclerotic cardiovascular disease. While synthetic inhibitors of microsomal triglyceride transfer protein (MTP) have shown potential in lowering LDL-C, they are associated with adverse effects. This study explores a novel approach by screening natural products to identify plant extracts that down-regulate MTP gene expression, aiming to reduce hyperlipidaemia with fewer side effects. Modulating MTP expression, rather than direct inhibition, offers a promising avenue for lowering plasma lipids and mitigating cardiovascular risk. Various plant extracts were examined for their potential as MTP down-regulators, with Liquorice root and Pomegranate rind extracts demonstrating the highest efficacy. Additionally, the study assessed the total phenolic content of these extracts, revealing their ­antioxidant capacity. This research provides a foundation for further investigation into bioactive molecules as potential anti-hyperlipidemic agents with improved safety profiles, addressing a critical need in cardiovascular disease prevention.

Zuogui Jiangtang Qinggan Formula improves glucolipid metabolism in type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease by regulating FoxO1/MTP/APOB signaling pathway

This study aimed to investigate the effect and mechanism of Zuogui Jiangtang Qinggan Formula(ZGJTQG) on the glucolipid metabolism of type 2 diabetes mellitus(T2DM) complicated with non-alcoholic fatty liver disease(NAFLD). NAFLD was induced by a high-fat diet(HFD) in MKR mice(T2DM mice), and a model of T2DM combined with NAFLD was established. Forty mice were randomly divided into a model group, a metformin group(0.067 g·kg~(-1)), and high-and low-dose ZGJTQG groups(29.64 and 14.82 g·kg~(-1)), with 10 mice in each group. Ten FVB mice of the same age were assigned to the normal group. Serum and liver tissue specimens were collected from mice except for those in the normal and model groups after four weeks of drug administration by gavage, and fasting blood glucose(FBG) and fasting insulin(FINS) levels were measured. The levels of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL) were detected by the single reagent GPO-PAP method. Very low-density lipoprotein(VLDL) was detected by enzyme-linked immunosorbent assay(ELISA). Alanine aminotransferase(ALT) and aspartate ami-notransferase(AST) were determined by the Reitman-Frankel assay. The pathological changes in the liver were observed by hematoxylin-eosin(HE) staining and oil red O staining. Real-time fluorescence-based quantitative polymerase chain reaction(real-time PCR) and Western blot were adopted to detect the mRNA and protein expression of forkhead transcription factor O1(FoxO1), microsomal triglyceride transfer protein(MTP), and apolipoprotein B(APOB) in the liver. The results showed that high-dose ZGJTQG could signi-ficantly reduce the FBG and FINS levels(P<0.05, P<0.01), improve glucose tolerance and insulin resistance(P<0.05, P<0.01), alleviate the liver damage caused by HFD which was reflected in improving liver steatosis, and reduce the serum levels of TC, TG, LDL, VLDL, ALT, and AST(P<0.05, P<0.01) in T2DM mice combined with NAFLD. The findings also revealed that the mRNA and protein expression of FoxO1, MTP, and APOB in the liver was significantly down-regulated after the intervention of high-dose ZGJTQG(P<0.05, P<0.01). The above study showed that ZGJTQG could effectively improve glucolipid metabolism in T2DM combined with NAFLD, and the mechanism was closely related to the regulation of the FoxO1/MTP/APOB signaling pathway.

Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.

Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose‐derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline‐rich acidic protein 1 (PRAP1) complex inhibited zinc finger E‐box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose‐derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC.

Chemosensing of fat digestion by the expression pattern of GPR40, GPR120, CD36 and enteroendocrine profile in sheep

Gastrointestinal tract (GIT) epithelial cells detect nutrients in the lumen via G-protein coupled receptors (GPRs) located in the gut epithelial cells especially in enteroendocrine cells. Dietary free fatty acids (FFA) are the major energy source and also acts as signalling molecules for FFA receptors. Long chain fatty acids (LCFA) activate LCFA receptors, GPR40/FFAR1 and GPR120/FFAR4 which trigger intracellular signalling and release gut hormones or modifies gene expression that facilitate fat digestion and absorption. However, there is a paucity of information on chemosensing of nutrients and digestion in ruminants. Hence, present study was aimed to evaluate chemosensing of fat digestion and absorption by the expression pattern of GPR40, GPR120, chylomicron forming genes, fatty acid translocase (CD36/FAT), microsomal triglyceride transfer protein (MTTP) and apolipoprotein B (APOB) in the various segments of GIT in sheep supplemented with calcium salts of long chain fatty acids (CSLCFAs) along with the secretory patterns of gut peptides cholecystokinin (CCK) and peptide tyrosine tyrosine (PYY). The study was carried out for a period 60 days with eighteen adult ewes of 8–12 months of age and they were divided into three groups with six animals each as group-I, group-II and group-III. All the experimental animals were stall fed with a basal diet and maintained as per animal husbandry standards. Group-II and group-III were supplemented additionally with 3% and 5% CSLCFAs, respectively on dry matter intake. The results from the study indicated that the supplementation of CSLCFAs upregulated (P < 0.05) the relative mRNA expression of GPR40 and GPR120 in the various segments of GIT of sheep in correspondence to level of dietary fat. Abundance of mRNA expression of CD36, MTTP and APOB increased (P < 0.05) in the GIT of sheep in accordance to quantity of LCFAs in the diet where these genes facilitate fatty acid uptake. Feeding of CSLCFAs enhanced (P < 0.05) pre-feeding level of CCK from day 15 onwards, whereas, post-feeding CCK and PYY increased in all the experimental sheep. However, the increase was higher (P < 0.05) in sheep supplemented with CSLCFAs by 10.80 ± 1.45% and 14.25 ± 1.17%, respectively in comparison to group-I. The comprehensive results of the study concluded that feeding of additional CSLCFAs upregulated the expression of GPR40, GPR120, CD36, and chemosensing of LCFAs by these genes triggered the signalling transduction that enhanced CCK and PYY levels to facilitate fat digestion and absorption in accordance with quantity of dietary fat. This was further evident from the significant upregulation of MTTP and APOB in the various segments of GIT supported the high content of dietary fat at cellular fat metabolism in the gut that regulates the fatty acid uptake.

DLp/HDL-BGBP and MTP Cloning and Expression Profiles During Embryonic Development in the Mud Crab Scylla paramamosain.

Lipids are the main energy source for embryonic development in oviparous animals. Prior to the utilization and catabolism, lipids are primarily transported from the yolk sac to embryonic tissues. In the present study, cDNA encoding a circulatory large lipid transfer protein (LLTP) superfamily member, the precursor of large discoidal lipoprotein (dLp) and high-density lipoprotein/β-1,3-glucan-binding protein (HDL-BGBP), named dLp/HDL-BGBP of 14,787 bp in length, was cloned from the mud crab Scylla paramamosain. dLp/HDL-BGBP was predicted to encode a 4,831 amino acids (aa) protein that was the precursor of dLp and HDL-BGBP, which were both detected in hemolymph by liquid chromatography–mass spectrometry (LC-MS/MS) analysis. For the intracellular LLTP, three microsomal triglyceride transfer protein (MTP) cDNAs of 2,905, 2,897, and 3,088 bp in length were cloned from the mud crab and were predicted to encode MTP-A of 881 aa, MTP-B of 889 aa, and MTP-C of 919 aa, respectively, which were different merely in the N-terminal region and shared an identical sequence of 866 aa. During embryonic development, the expression level of dLp/HDL-BGBP consecutively increased from the early appendage formation stage to the eye pigment-formation stage, which indicated that HDL-BGBP is probably the scaffolding protein for yolk lipid. For the MTP gene, MTP-C accounted for ~70% of MTP mRNA from the blastocyst stage to the nauplius stage, as well as the pre-hatching stage; MTP-C and MTP-A expression levels were comparable from the early appendage formation stage to the late eye pigment-formation stage; MTP-A was extremely low in blastocyst and gastrula stages; MTP-B was expressed at a relatively low-level throughout embryo development. The variations in the expression profiles among MTP transcripts suggested that MTP might play roles in the lipid droplet maturation and lipoprotein assembly during embryonic development.

Berberine ameliorates nonalcoholic fatty liver disease by decreasing the liver lipid content via reversing the abnormal expression of MTTP and LDLR

The global incidence of nonalcoholic fatty liver disease (NAFLD) is increasing. The present study explored the effect and mechanism of berberine (BBR) on NAFLD in rats. Thirty-five Sprague-Dawley rats were randomly divided into the control and NAFLD groups, which were fed a normal diet or high-fat diet, respectively, for 8 weeks. Hematoxylin and eosin staining was performed on liver tissues and establishment of the NAFLD model was confirmed by microscopy. NAFLD rats were subsequently randomly subdivided and treated with saline or BBR for 8 weeks. The liver wet weight of rats in each group was measured, the liver tissue structure was observed by microscopy, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), fasting blood glucose (FBG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were detected using a semi-automatic biochemical detector. Reverse transcription-quantitative PCR and western blotting were performed to determine the mRNA and protein expression levels of microsomal triglyceride transfer protein (MTTP), apolipoprotein B and low-density lipoprotein receptor (LDLR). Compared with the control group, the liver wet weight of the NAFLD rats was higher; the liver showed obvious fatty degeneration and liver TG levels increased significantly, as did serum levels of ALT, AST, TC, TG, FBG, HDL and LDL, while expression of MTTP and LDLR significantly decreased. Compared with the saline-treated NAFLD rats, the BBR-treated rats had reduced liver wet weight, improved liver steatosis and a significant decrease in liver TG levels, while ALT, AST, TC, TG, and LDL serum levels significantly decreased and MTTP levels were significantly upregulated. In conclusion, BBR treatment ameliorated the fatty liver induced by a high-fat diet in rats. Furthermore, BBR reversed the abnormal expression of MTTP and LDLR in rats with high-fat diet induced-NAFLD. The present findings suggest that fatty liver could be improved by BBR administration, via reversing the abnormal expression of MTTP and LDLR and inhibiting lipid synthesis.

Dietary egg white protein hydrolysate improves orotic acid-induced fatty liver in rats by promoting hepatic phospholipid synthesis and microsomal triglyceride transfer protein expression

We investigated the effects of egg white protein hydrolysates (EWH) on orotic acid (OA)-induced nonalcoholic fatty liver (NAFL) in rats. Effects of the egg white protein (EWP) and EWH were also compared. Four groups of male Sprague-Dawley rats were separately fed AIN-76-based diets, supplemented with 20% casein for control, or with 1% OA, together with either 20% casein (OA), 20% EWP, or 20% EWH, respectively, for 3 d (developing stage) and 14 d (developed stage). In both feeding periods, animals from the OA group showed higher accumulation hepatic triacylglycerol (TAG) compared with those from the control group. In the 14-d experiment, dietary EWP and EWH significantly reduced the hepatic TAG levels. Intake of EWP reduced liver fat in OA-fed rats by 61%, while EWH reduced it by 92%. In addition, EWH restored the OA-induced high serum-TAG level to that seen in the control group. The 3 d experiment showed that consumption of EWH improved the expression of hepatic MTP, that was reduced by OA, without changing Mttp gene expression. It also increased the hepatic synthesis of PC and PE by enhancing the transcription of Pcyt1 and Pemt genes. Inclusion of EWP and EWH in the diet improves the OA-induced NAFL. EWH reduces the liver TAG better than EWP, and works more rapidly. Dietary EWH ameliorates OA-induced NAFL by promoting the secretion of hepatic TAG.

Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway

Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in inflammatory bowel disease (IBD) patients with unclear etiology. In the current study we assessed the contribution of colonic inflammation to NAFLD development and the underlying mechanism in a mouse model for IBD. Our results showed that dextran sulfate sodium (DSS)-induced gut colitis directly led to hepatic inflammation, injury and further exacerbated hepatic steatosis caused by high fat diet (HF) feeding. The essential genes assessment, hepatic metabolic analysis and triglyceride-rich very low-density lipoprotein (VLDL-TG) secretion assays revealed a higher β-oxidation of fatty acids (FAs) but impaired VLDL-TG secretion in liver of DSS-treated mice. Disruption of the intestinal barrier by DSS promoted liver inflammation, which strongly suppressed hepatic VLDL-TG secretion and further aggravated HF-induced VLDL-TG secretion impairment through down-regulation of apolipoprotein B (APOB), hence promoting the storage of triglycerides (TG) in the liver. Inflammation induced by mixed proinflammatory cytokines or LPS obviously inhibited the expression of microsomal triglyceride transfer protein (MTP) and APOB expression and subsequently increased TG content via the suppression of HNF4α in mouse primary hepatocytes. In addition, the downregulation of MTP and APOB by proinflammatory cytokines was also rescued through activating Hnf4α by cortisol. Altogether, our results demonstrated that chronic inflammation exacerbated hepatic steatosis by inhibiting the secreting of hepatic VLDL-TG through HNF4α pathway, suggesting that restoring hepatic VLDL-TG secretion may be a novel strategy for treatment of NAFLD in IBD.

Large lipid transfer proteins in hepatopancreas of the mud crab Scylla paramamosain

Large lipid transfer proteins (LLTPs) are extensively involved in various physiological processes. In the present study, five LLTP sequences encoding apolipocrustacein 1 (apoCr 1), apoCr 2, precursor of the large discoidal lipoprotein (dLp) and high density lipoprotein/β-glucan binding protein (HDL-BGBP) (dLp-BGBP), microsomal triglyceride transfer protein (MTP) and clotting protein (CP) were identified in the hepatopancreas of Scylla paramamosain. Of these, apoCr 2, dLp-BGBP, and MTP were newly identified in this species, and the former two proteins were classified into the APO family while the later into the MTP family in phylogenetic trees. The apoCr 1 expression level was dramatically increased in the hepatopancreas towards ovarian maturation, which was extremely greater than that in the ovaries concurrently, likely to meet the considerable requirements of yolk protein and lipids for embryo development. The dLp-BGBP expression level in male crabs was comparable to that in female crabs, supporting HDL-BGBP acts as a major circulatory lipid carrier. The close phylogenetic relationship between dLp-BGBP and the scaffolding protein of lipid transfer particle implied dLp might facilitate lipid transfer between the hepatopancreas and HDL-BGBP-containing lipoproteins. The MTP expression level was positively related to ovarian development in both the hepatopancreas and ovaries, indicating MTP may be involved in lipoprotein assembly in the hepatopancreas and lipid droplet maturation in the ovaries. CP may play a crucial role in embryo development based on high expression level observed in the testes of mature crabs. Our findings provide novel insights into LLTP superfamily members and their functions in decapods.

Andrographolide modulates HNF4α activity imparting on hepatic metabolism

Hepatic nuclear factor 4 alpha (HNF4α) drives the expression of apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTP) and phospholipase A2 G12B (PLA2G12B), governing hepatic very-low-density lipoprotein (VLDL) production and secretion. Andrographolide (AP) is a major constituent isolated from Andrographis paniculata. We found that AP can disrupt the interaction between HNF4α and its coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Virtual docking and mutational analysis indicated that arginine 235 of HNF4α is essential for binding to AP. As a consequence of antagonizing the activity of HNF4α, AP suppresses the expression of ApoB, MTP and PLA2G12B and reduces the rate of hepatic VLDL secretion in vivo. AP additionally reduced gluconeogenesis via down-regulating the expression of HNF4α target genes phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pc). Collectively, our results suggest that AP affects liver function via modulating the transcriptional activity of HNF4α.

White tea and its active polyphenols lower cholesterol through reduction of very-low-density lipoprotein production and induction of LDLR expression

Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.

Reduced Serum Cholesterol and Triglyceride Levels in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet (CDAHFD)-Induced Mouse Model of Non-alcoholic Steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic seatohepatitis (NASH) is one of the major health problems world wide, because of increased abdominal obesity. To date, specific and effective medications to treat or prevent NAFLD/NASH have not been established. To identify appropriate molecular targets for that purpose, suitable animal models of NAFLD/NASH have been explored. A choline-deficient amino acid-defined high fat diet (CDAHFD)-induced mouse model of NASH has been developed. However, its relevance to human NASH, including serum lipid profiles, have not been clearly defined. In this study, we have revealed that mice fed CDAHFD showed significantly lowerd serum total cholesterol and triglyceride (TG) levels, in addition to reduced body weight (BW). Furthermore, hepatic microsomal triglyceride transfer protein (MTP) expression was significantly downregulated in CDAHFD-fed mice. Thus, the current CDAHFD-fed mouse model has points that are distinct from human NAFLD/NASH, in general, which is based upon abdominal obesity.

Valproic acid affects fatty acid and triglyceride metabolism in HepaRG cells exposed to fatty acids by different mechanisms

Treatment with valproate is associated with hepatic steatosis, but the mechanisms are not fully elucidated in human cell systems. We therefore investigated the effects of valproate on fatty acid and triglyceride metabolism in HepaRG cells, a human hepatoma cell line. In previously fatty acid loaded HepaRG cells, valproate impaired lipid droplet disposal starting at 1 mM after incubation for 3 or 7 days. Valproate increased the expression of genes associated with fatty acid import and triglyceride synthesis, but did not relevantly affect expression of genes engaged in fatty acid activation. Valproate impaired mitochondrial fatty acid metabolism by inhibiting β-ketothiolase and the function of the electron transport chain, which was associated with increased mitochondrial reactive oxygen species production. Valproate increased the mitochondrial DNA copy number per HepaRG cell, possibly as a consequence of impaired mitochondrial function. Valproate decreased the hepatocellular mRNA and protein expression of the fatty acid binding protein 1 (FABP1) and of the microsomal triglyceride transfer protein (MTTP) at 1 mM and increased the hepatocellular concentration of free fatty acids. Furthermore, valproate decreased protein expression and excretion of ApoB100 in HepaRG cells at 1 mM, reflecting impaired formation and excretion of very low-density lipoprotein (VLDL). In conclusion, valproate increased the hepatocellular triglyceride content by multiple mechanisms, whereby impaired expression of FABP1 and MTTP as well as impaired VLDL formation and excretion appeared to be dominant. Valproate caused cell death mainly by apoptosis, which may be a consequence of mitochondrial oxidative stress and increased hepatocellular concentration of free fatty acids.