Shao-Ching Hung

Hypocholesterolemic Effects of Hydroxypropyl Methylcellulose Are Mediated by Altered Gene Expression in Hepatic Bile and Cholesterol Pathways of Male Hamsters

Hydroxypropyl methylcellulose (HPMC), a semisynthetic, nonfermentable soluble dietary fiber, is not absorbed by the body, but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretions and decreases intestinal cholesterol absorption, all of which may indirectly affect hepatic lipid metabolism. We measured the expression of hepatic genes involved in cholesterol, bile acid, and fatty acid metabolism in hamsters fed diets containing 39% of energy as fat and 5% of weight as HPMC or microcrystalline cellulose (control) for 4 wk. HPMC-fed hamsters gained significantly less body weight than the control group but did not differ in food intake. They had significantly lower plasma triglyceride and total-, VLDL-, HDL-, and LDL-cholesterol concentrations and hepatic total lipid, total and free cholesterol and triglyceride concentrations than controls. Compared with controls, HPMC-fed hamsters had greater levels of mRNA for CYP7A1 (cytochrome P450 7A1; 8-fold of control; P < 0.05), CYP51 (lanosterol 14alpha-demethylase; 5.3-fold of control; P < 0.05), and HMG-CoAR (3-hydroxy-3-methylglutaryl CoA reductase; 1.8-fold of control; P < 0.05). The plasma total cholesterol concentrations from both the control and HPMC groups were inversely correlated with expression of hepatic CYP7A1 (r = -0.54; P < 0.05), CYP51 (r = -0.79; P < 0.005), and HMG-CoAR (r = -0.75; P < 0.005) genes. This suggests that HPMC supplementation affected both cholesterol and bile acid synthesis. Our data confirm that altered hepatic expression of lipid metabolism-related genes, possibly due to modulation of fecal bile acid excretion and intestinal cholesterol absorption, contributes to the lipid-lowering effects of HPMC.

The nonfermentable dietary fiber hydroxypropyl methylcellulose modulates intestinal microbiota

Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited. To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high‐fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low‐fat diet (LFD). Compared to control treatment, both LFD and HPMC reduced weight gain (11.8 and 5.7 g, respectively), plasma cholesterol (23.1 and 19.6%), and liver triglycerides (73.1 and 44.6%), and, as revealed by 454‐pyrosequencing of the microbial 16S rRNA gene, decreased microbial α‐diversity and differentially altered intestinal microbiota. Both LFD and HPMC increased intestinal Erysipelotrichaceae (7.3‐ and 12.4‐fold) and decreased Lachnospiraceae (2.0‐ and 2.7‐fold), while only HPMC increased Peptostreptococcaceae (3.4‐fold) and decreased Ruminococcaceae (2.7‐fold). Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations. This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism.—Cox, L. M., Cho, I., Young, S. A., Kerr Anderson, W. H., Waters, B. J., Hung, S.‐C., Gao, Z., Mahana, D., Bihan, M., Alekseyenko, A. V., Methé, B. A., Blaser, M. J. The nonfermentable dietary fiber hydroxypropyl methylcellulose modulates intestinal microbiota. FASEB J. 27, 692–702 (2013). www.fasebj.org

Dietary fiber improves lipid homeostasis and modulates adipocytokines in hamsters.

Background:  The hypocholesterolemic and hypoglycemic effects of various natural and semisynthetic dietary fibers have been studied for their potential use in the prevention and improvement of metabolic syndrome. Of these dietary fibers, hydroxypropyl methylcellulose (HPMC) has been shown to lower plasma cholesterol and reduce weight gain. However, the underlying mechanisms are not known. In the present study, we examined associations between plasma adipocytokine levels and both lipid metabolism and insulin sensitivity after HPMC intake in golden Syrian hamsters. In addition, endogenous adiponectin from hamster plasma was purified and characterized.

Effect of hydroxypropyl methylcellulose on obesity and glucose metabolism in a diet-induced obesity mouse model

Background:  To investigate the effect of hydroxypropyl methylcellulose (HPMC) on weight loss and metabolic disorders associated with obesity using a high‐fat diet‐induced obese mouse model under a high‐fat diet regimen.

Determination of F2-isoprostanes in urine by online solid phase extraction coupled to liquid chromatography with tandem mass spectrometry.

F(2)-isoprostanes are a unique class of prostaglandin-like compounds formed in vivo, which have been established as biomarkers of oxidative stress. Accurate analysis has been challenging due to lack of specificity for the isoforms of isoprostanes and lengthy sample preparation procedures to enable trace quantitative analysis. A quantitative analytical method was developed for the determination of F(2)-isoprostanes in rat and hamster urine by online solid phase extraction (SPE) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS). The online SPE LC-MS/MS procedure has significant advantages over alternative methods with respect to specificity, sensitivity, simplicity, and speed. The assay enables the detection of iPF(2alpha)-III, iPF(2alpha)-IV, and iPF(2alpha)-VI over a linear dynamic range of 0.1-50 ng/mL in rat urine samples. This range covers the basal levels of these F(2)-isoprostanes. The limit of quantitation (LOQ) for the standard isoprostanes was about 0.3 ng/mL. The average recoveries ranged from 73 to 115% depending upon the individual F(2)-isoprostane isomers in rat urine. Additionally, the method was used to determine increases of endogenous urine iPF(2alpha)-VI and iPF(2alpha)-III in hamsters challenged with either low-fat or high-fat diets.

Dietary hydroxypropyl methylcellulose increases excretion of saturated and trans fats by hamsters fed fast food diets.

In animal studies, hydroxypropyl methylcellulose (HPMC) intake results in increased fecal fat excretion; however, the effects on dietary saturated fatty acids (SATs) and trans-fatty acids (TRANS) remain unknown. This study investigated the effect of HPMC on digestion and absorption of lipids in male Golden Syrian hamsters fed either freeze-dried ground pizza (PZ), pound cake (PC), or hamburger and fries (BF) supplemented with dietary fiber from either HPMC or microcrystalline cellulose (MCC) for 3 weeks. We observed greater excretion of SATs and TRANS by both diets supplemented with HPMC or MCC as compared to the feed. SAT, TRANS, and unsaturated fatty acids (UNSAT) contents of feces of the PZ diet supplemented with HPMC were 5-8 times higher than diets supplemented with MCC and tended to be higher in the PC- and BF-HPMC supplemented diets as well. We also observed significant increases in fecal excretion of bile acids (2.6-3-fold; P < 0.05), sterols (1.1-1.5-fold; P < 0.05), and unsaturated fatty acids (UNSAT, 1.7-4.5-fold; P < 0.05). The animal body weight gain was inversely correlated with the excretion of fecal lipid concentrations of bile acids (r = -0.56; P < 0.005), sterols (r = -0.48; P < 0.005), SAT (r = -0.69; P < 0.005), UNSAT (r = -0.67; P < 0.005), and TRANS (r = -0.62; P < 0.005). Therefore, HPMC may be facilitating fat excretion in a biased manner with preferential fecal excretion of both TRANS and SAT in hamsters fed fast food diets.

Effects of cationic hydroxyethyl cellulose on glucose metabolism and obesity in a diet-induced obesity mouse model.

Background:  To investigate the effect of a new soluble fiber, namely cationic hydroxyethyl cellulose (cHEC), on weight loss and metabolic disorders associated with obesity using a high‐fat diet‐induced obese mouse model.

Quantification of the Sulfated Cholecystokinin CCK-8 in Hamster Plasma Using Immunoprecipitation Liquid Chromatography-Mass Spectrometry/Mass Spectrometry

Cholecystokinin (CCK) and the different molecular forms of CCK are well established as biomarkers for satiety but accurate analysis has been limited by the multiple naturally occurring forms and extensive similarities to gastrin. Changes in levels of one form, CCK-8, a naturally occurring eight amino acid peptide of CCK, have been correlated with satiety responses. Endogenous CCK-8 has not been well characterized in Syrian Golden hamsters, an important model in the study of fat uptake and digestion. We have cloned and sequenced hamster CCK and identified and characterized endogenous CCK-8 from hamster plasma. Hamster CCK-8 is composed of eight amino acid residues which are highly conserved among other species. Following accurate identification and characterization of hamster CCK-8, we have developed a highly specific and sensitive immunoprecipitation based LC-MS/MS assay for its quantification. The present assay enables determination of active CCK-8 over a concentration range from 0.05 to 2.5 ng/mL in hamster plasma samples. This range covers both the basal and postprandial levels of CCK-8. Method performance validation samples were examined at three concentrations replicated over the course of 4 days. The assay accuracy (percent relative error, % RE) average was 11.3% with a precision (percent coefficient of variation, % CV) of 15.5% over all samples in this 4 day period. Additionally, the method was used to determine increases of endogenous plasma CCK-8 in hamsters challenged with a high-fat meal.

Effects of cationic hydroxyethyl cellulose on dyslipidemia in hamsters.

Cationic hydroxyethyl cellulose (cHEC) was supplemented in a high-fat diet to determine if this new soluble fiber had an effect on hypercholesterolemia and dyslipidemia associated with cardiovascular disease using Golden Syrian hamster as an animal model. Supplementation of 3-5% cHEC in a high-fat diet for 4 weeks led to significant weight gain reduction in hamsters. In addition, significant decreases in adipose and liver weights, concentrations of plasma total, VLDL, and LDL cholesterol, and hepatic lipids were shown. No significant improvements in glucose and insulin levels were observed with cHEC; however, a significant increase in plasma adiponectin and a decrease in leptin were observed. As compared with controls, 8% cHEC-fed hamsters had greater levels of mRNA for CYP7A1 (cytochrome P450 7A1; 2-fold of control; P < 0.05), CYP51 (lanosterol 14α-demethylase; 6-fold of control; P < 0.05), and LDLR (LDL receptor; 1.5-fold of control) in the liver. These findings suggest the possibility of the use of cHEC for cholesterol reduction and beneficial effects on the cardiovascular risk factors.