Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors

This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r = 0.80, P < 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.     

Hypolipidemic Activity and Mechanism of Action of Sargassum fusiforme Polysaccharides

Sargassum fusiforme polysaccharide (SFP) is a kind of biologically active macromolecule with biological functions. In this study, oxidative stress and high-fat HepG2 cell models were established to investigate its lipid-lowering activity and mechanism of action. It was found that SFP and its two isolated fractions had antioxidant effects on the cells. It was also found the polysaccharides decreased the content of total cholesterol and total triglyceride in the high-fat cells. RT-qPCR assays revealed that the three polysaccharides down-regulated the mRNA expression level of ACC, PPARγ, and SREBP-2. It could be concluded that the hypolipidemic effect of SFPs is achieved via multiple pathways, including the regulation on the expression level of lipid metabolism-related key enzymes and factors, and binding with bile acids. The hypolipidemic effect of SFPs could be partially due to their antioxidant activity. SFPs developed in the present work have potential as ingredients of functional foods with hypolipidemic effect.     

Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats

Background

Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated.

Objective

This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators.

Methods

SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA.

Results

The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention.

Conclusion

Octreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes.     

Mechanisms underlying different responses of plasma triglyceride to high-fat diets in hamsters and mice: Roles of hepatic MTP and triglyceride secretion

Hypertriglyceridemia, closely associated with insulin resistance, is induced on high-fat diets (HFD) in humans but not in mouse models. Mechanisms underlying this species difference are still unclear. Hamsters resemble humans in lipoprotein metabolism. Here by comparing the responses to HFD in hamsters and mice, we found that hepatic TG secretion, MTP expression and plasma free fatty acid (FFA) level were increased in hamsters on HFD feeding but decreased in mice. Although hepatic steatosis and de novo lipogenesis were induced by HFD feeding in both models, cholesterol biosynthesis was inhibited in mice but not in hamsters. Moreover, in insulin deficient state, HFD increased plasma TG level, hepatic TG secretion, MTP expression and plasma FFA level in both models. In summary, distinct changes of MTP expression, in correlation with hepatic TG secretion, underlie the opposite responses of plasma TG levels to high-fat diets in hamsters and mice. Furthermore, hepatic TG secretion and MTP expression seems to be associated with plasma FFA level and cholesterol biosynthesis but not hepatic steatosis or de novo lipogenesis.     

Tripterygium regelii decreases the biosynthesis of triacylglycerol and cholesterol in HepG2 cells

In the course of screening to find a plant material decreasing the activity of triacylglycerol and cholesterol, we identified Tripterygium regelii (TR). The methanol extract of TR leaves (TR-LM) was shown to reduce the intracellular lipid contents consisting of triacylglycerol (TG) and cholesterol in HepG2 cells. TR-LM also downregulated the mRNA and protein expression of the lipogenic genes such as SREBP-1 and its target enzymes. Consequently, TR-LM reduced the TG biosynthesis in HepG2 cells. In addition, TR-LM decreased SREBP2 and its target enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. In this study, we evaluated that TR-LM attenuated cellular lipid contents through the suppression of de novo TG and cholesterol biosynthesis in HepG2 cells. All these taken together, TR-LM could be beneficial in regulating lipid metabolism and useful preventing the hyperlipidemia and its complications, in that liver is a crucial tissue for the secretion of serum lipids.     

Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model

Fenofibrate is the ligand for PPARalpha subtype that mediates the action of its agonists' in lipid metabolism. How fibrate exerts hypolipidemic effect? The mechanism is studied in a newly developed high-fat fructose enriched diet induced dyslipidemia-diabetic hamster model. Fenofibrate lowered the basal plasma lipids like TC, TG, PL, FFA, glycerol, VLDL, and LDL, but HDL was increased. The activity of lipoprotein lipase in liver, adipose tissue, and small intestine was upregulated. However, that of triglyceride lipase was downregulated in liver. It has also improved the insulin secretion and plasma glucose lowering, caused by impairment in insulin secretion due to high-fat load. The drug was found effective in reducing body weight and diet due to rise in leptin level. Fenofibrate also enhanced the fecal excretion of total lipids, cholic acid, and deoxycholic acid probably by the activation of 7alpha cholesterol hydroxylase enzyme. Thus, causing broad-spectrum lipid lowering along with inhibition of hepatic lipid biosynthesis and maintaining lipid-glucose homeostasis.     

Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a approximately 27% (P < 0.05) increase in cholesterol but approximately 29% reduction (P = 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7alpha hydroxylase and liver X receptor-alpha (LXRalpha) were reduced by approximately 50% (P < 0.01) and approximately 34% (P < 0.01), respectively. As LXRalpha regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an approximately 43% (P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by approximately 35% (P = 0.01), fatty acid synthase by approximately 18% (P = 0.05), and diacylglycerol acyltransferase by approximately 19% (P = 0.03). Furthermore, protein levels of CD36 were reduced by approximately 27% (P = 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7alpha hydroxylase and its regulator LXRalpha, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways.     

A low fish oil inhibits SREBP-1 proteolytic cascade,while a high-fish-oil feeding decreases SREBP-1 mRNA in mice liver: relationship to anti-obesity

Rodents fed fish oil showed less obesity with a reduction of triglyceride synthesis in liver, relative to other dietary oils, along with a decrease of mature form of sterol regulatory element binding protein-1 (SREBP-1) and activation of peroxisome proliferator-activated receptor alpha (PPARalpha). Decrease of mature SREBP-1 protein by fish oil feeding was due to either inhibition of SREBP-1 proteolytic cascade or to decrease of its mRNA. To clarify its mechanism and relation to antiobesity effect, mice were fed fish oil in a range from 10 to 60 energy percent (en%). Fish oil feeding decreased body weight and fat mass in a dose-dependent manner, in parallel with PPARalpha activation and a decrease of SREBP-1 mRNA. However, compared with 0 en% fish oil feeding, 10 en% fish oil feeding decreased mature SREBP-1 protein by 50% with concomitant decreases of lipogenic genes, while precursor SREBP-1 protein rather increased by 1.3-fold. These data suggest that physiological doses of fish oil feeding effectively decrease expression of liver lipogenic enzymes by inhibiting SREBP-1 proteolytic cascade, while substantial decrease of SREBP-1 expression is observed in its pharmacological doses, and that activation of PPARalpha rather than SREBP-1 decrease might be related to the antiobesity effect of fish oil feeding.