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Nicholas O Davidson

Publications and source records attributed to Nicholas O Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis.

Unlike the livers of humans and mice, and most hepatoma cells, which accumulate triglycerides when treated with microsomal triglyceride transfer protein (MTP) inhibitors, L35 rat hepatoma cells do not express MTP and cannot secrete very low density lipoprotein (VLDL), yet they do not accumulate triglyceride. In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis. FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL. In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL. We used these hepatoma cells to elucidate how a conserved DR1 promoter element present in the promoters of L-FABP and MTP affects transcription, expression, and VLDL production. In FAO cells, the DR1 elements of both L-FABP and MTP promoters are occupied by peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (RXRalpha), with which PGC-1beta activates transcription. In contrast, in L35 cells the DR1 elements of both L-FABP and MTP promoters are occupied by chicken ovalbumin upstream promoter transcription factor II, and transcription is diminished. The combined findings indicate that peroxisome proliferator-activated receptor alpha-RXRalpha and PGC-1beta coordinately up-regulate L-FABP and MTP expression, by competing with chicken ovalbumin upstream promoter transcription factor II for the DR1 sites in the proximal promoters of each gene. Additional studies show that ablation of L-FABP prevents hepatic steatosis caused by treating mice with an MTP inhibitor. Our findings show that reducing both L-FABP and MTP is an effective means to reduce VLDL secretion without causing hepatic steatosis.

Animals↗
PubMed2006

Type 2 diabetes mellitus: the impact on colorectal adenoma risk in women.

OBJECTIVES: Increased risk for colorectal cancer (CRC) has been associated with type 2 diabetes. Despite several studies linking insulin resistance to increased CRC risk, there are limited data on colorectal adenoma risk in diabetic women. We hypothesized that diabetic women would have increased rates of colorectal adenomas relative to a group of nondiabetic women. METHODS: Colorectal adenoma rates were determined in 100 estrogen-negative women with type 2 diabetes mellitus and compared with 500 nondiabetic, estrogen-negative controls. Adenomas were defined as any adenoma or advanced adenoma (villous or tubulovillous features, size >1 cm or high-grade dysplasia). A multivariate model including age, race, diabetes, hypertension, hypercholesterolemia, body mass index, and nonsteroidal anti-inflammatory drug status was used to determine the independent effects of diabetes on colorectal adenoma incidence. RESULTS: Diabetics as compared with nondiabetics had greater rates of any adenoma (37%vs 24%, p= 0.009) and advanced adenomas (14%vs 6%, p= 0.009). Two hundred forty-five obese subjects compared with 355 nonobese subjects had a higher rate of any adenoma (32%vs 22%, p= 0.001). Obese diabetics compared with nonobese, nondiabetics had greater rates of any adenoma (42%vs 23%, p< or = 0.001) and advanced adenomas (19%vs 7%, p< or = 0.001). Multivariate analysis showed that adenomas and advanced adenomas were independently predicted by diabetes (p < 0.05) and adenomas by age. DISCUSSION: Women with type 2 diabetes mellitus had higher rates of colorectal adenomas as compared with lean and nondiabetic women. This finding adds to the evidence that type 2 diabetes is an important factor in the progression of the adenoma-carcinoma sequence.

Adenoma↗
PubMed2006

PI3-kinase activity modulates apo B available for hepatic VLDL production in apobec-1-/- mice.

Insulin regulates hepatic VLDL production by activation of phosphatidylinositide 3-kinase (PI3-kinase) which decreases apo B available for lipid assembly. The current study evaluated the dependence of the VLDL apolipoprotein B (apo B) pathway on PI3-kinase activity in vivo. VLDL production was examined in B100 only, apo B mRNA editing catalytic subunit 1 (apobec-1(-/-)) mice, using the Triton WR 1339 method. Glucose injection suppressed VLDL triglyceride production by 28% in male and by 32% in female mice compared with saline-injected controls. When wortmannin was injected to inhibit PI3-kinase, VLDL triglyceride production was increased by 52% in males and by 89% in females, and VLDL B100 levels paralleled triglyceride changes. Pulse-chase experiments in primary mouse hepatocytes showed that wortmannin increased net freshly synthesized B100 availability by >35%. To test whether physiological insulin resistance produced equivalent effects to wortmannin, we studied male apobec-1(-/-) mice who became hyperlipidemic on being fed a fructose-enriched diet. Fructose-fed apobec-1(-/-) mice had significantly higher VLDL triglyceride and B100 production rates compared with chow-fed mice, and rates were refractile to glucose or wortmannin. Hepatic VLDL triglyceride and B100 production in wortmannin-injected chow-fed mice equaled that observed in fructose-fed mice. Together, results suggest in vivo and in vitro that wortmannin-sensitive PI3-kinases maintain a basal level of VLDL suppression that is sensitive to changes in activation and that can increase VLDL production when PI3-kinase is inhibited to levels similar to those induced by insulin resistance.

APOBEC-1 Deaminase↗
PubMed2006

Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection.

The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine, but their role in the mature small bowel is unclear. With the use of a model of intestinal adaptation following partial small bowel resection, the role of Hh signaling in the adult gut was examined by determining the effects of blocking Hh signaling on the regenerative response following loss of functional surface area. Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was twofold more abundant than Gli1 and Gli2 and that bone morphogenetic protein (BMP)2 was most highly expressed compared with BMP1, -4, and -7. Following intestinal resection, the expression of Hh, Patched, Gli, and most BMP genes was markedly downregulated in the remnant ileum, and, in anti-Hh antibody-treated mice, expression of Patched 2 and Gli 1 was further suppressed. In Hh antibody-treated mice following resection, the enterocyte migration rate from crypt to villus tip was increased, and by 2 wk postoperation, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height, and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.

Adaptation, Physiological↗
PubMed2006

Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice.

Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable glucose intolerance and insulin resistance when fed a Western diet. Protection against obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal lipid secretion kinetics were significantly slower in both chow-fed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to carbohydrate, findings supported by an approximately threefold increase in serum lactate. Microarray analysis revealed increased expression of genes involved in lipid synthesis (fatty acid synthase, squalene epoxidase, hydroxy-methylglutaryl coenzyme A reductase), while genes involved in glycolysis (glucokinase and glycerol kinase) were decreased in L-Fabp(-/-) mice. Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use. (HEPATOLOGY 2006;44:1191-1205.).

Animals↗
PubMed2006

APOBEC3F and APOBEC3G mRNA levels do not correlate with human immunodeficiency virus type 1 plasma viremia or CD4+ T-cell count.

APOBEC3F and APOBEC3G (hA3F and hA3G) are part of an innate mechanism of antiretroviral defense. The human immunodeficiency virus type 1 (HIV-1) accessory protein Vif targets both proteins for proteasomal degradation. Using mRNA from peripheral blood mononuclear cells of 92 HIV-infected subjects not taking antiretroviral therapy and 19 HIV-uninfected controls, we found that hA3F (P < 0.001) and hA3G (P = 0.016) mRNA levels were lower in HIV-infected subjects and were positively correlated with one another (P = 0.003). However, we found no correlation in the abundance of either hA3F or hA3G mRNA with either viral load or CD4 counts in HIV-infected subjects.

APOBEC-3G Deaminase↗
PubMed2005

Compensatory increase in hepatic lipogenesis in mice with conditional intestine-specific Mttp deficiency.

Microsomal TG transfer protein (MTTP) is required for the assembly and secretion of TG (TG)-rich lipoproteins from both enterocytes and hepatocytes. Liver-specific deletion of Mttp produced a dramatic reduction in plasma very low density lipoprotein-TG and virtually eliminated apolipoprotein B100 (apoB100) secretion yet caused only modest reductions in plasma apoB48 and apoB48 secretion from primary hepatocytes. These observations prompted us to examine the phenotype following intestine-specific Mttp deletion because murine, like human enterocytes, secrete virtually exclusively apoB48. We generated mice with conditional Mttp deletion in villus enterocytes (Mttp-IKO), using a tamoxifen-inducible, intestine-specific Cre transgene. Villus enterocytes from chow-fed Mttp-IKO mice contained large cytoplasmic TG droplets and no chylomicron-sized particles within the secretory pathway. Chow-fed, Mttp-IKO mice manifested steatorrhea, growth arrest, and decreased cholesterol absorption, features that collectively recapitulate the phenotype associated with abetalipoproteinemia. Chylomicron secretion was reduced dramatically in vivo, in conjunction with an approximately 80% decrease in apoB48 secretion from primary enterocytes. Additionally, although plasma and hepatic cholesterol and TG content were decreased, Mttp-IKO mice demonstrated a paradoxical increase in both hepatic lipogenesis and very low density lipoprotein secretion. These findings establish distinctive features for MTTP involvement in intestinal chylomicron assembly and secretion and suggest that hepatic lipogenesis undergoes compensatory induction in the face of defective intestinal TG secretion.

Animals↗
PubMed2005

CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood.

CD36 mediates the transfer of fatty acids (FAs) across the plasma membranes of muscle and adipose cells, thus playing an important role in regulating peripheral FA metabolism in vivo. In the proximal intestine, CD36 is localized in abundant quantities on the apical surface of epithelial cells, a pattern similar to that of other proteins implicated in the uptake of dietary FAs. To define the role of CD36 in the intestine, we examined FA utilization and lipoprotein secretion by WT and CD36-null mice in response to acute and chronic fat feeding. CD36-null mice given a fat bolus by gavage or fed a high-fat diet accumulated neutral lipid in the proximal intestine, which indicated abnormal lipid processing. Using a model in which mice were equipped with lymph fistulae, we obtained evidence of defective lipoprotein secretion by directly measuring lipid output. The secretion defect appeared to reflect an impaired ability of CD36-null enterocytes to efficiently synthesize triacylglycerols from dietary FAs in the endoplasmic reticulum. In the plasma of intact mice, the reduced intestinal lipid secretion was masked by slow clearance of intestine-derived lipoproteins. The impaired clearance occurred despite normal lipoprotein lipase activity and likely reflected feedback inhibition of the lipase by FAs due to their defective removal from the plasma. We conclude that CD36 is important for both secretion and clearance of intestinal lipoproteins. CD36 deficiency results in hypertriglyceridemia both in the postprandial and fasting states and in humans may constitute a risk factor for diet-induced type 2 diabetes and cardiovascular disease.

Animals↗
PubMed2005

Reduced intestinal fat absorptive capacity but enhanced susceptibility to diet-induced fatty liver in mice heterozygous for ApoB38.9 truncation.

Fatty liver is prevalent in apolipoprotein B (apoB)-defective familial hypobetalipoproteinemia (FHBL). Similar to humans, mouse models of FHBL produced by gene targeting (apob(+/38.9)) manifest low plasma cholesterol and increased hepatic triglycerides (TG) even on a chow diet due to impaired hepatic VLDL-TG secretive capacity. Because apoB truncations shorter than apoB48 are expressed in the intestine, we examined whether FHBL mice may have limited capacity for intestinal dietary TG absorption. In addition, we investigated whether FHBL mice are more susceptible to diet-induced hepatic TG accumulation. Fat absorption capacity was impaired in apoB38.9 mice in a gene dose-dependent manner. Relative fractional fat absorption coefficients for apob(+/+), apob(+/38.9), and apob(38.9/38.9) were 1.00, 0.96, and 0.71, respectively. To raise hepatic TG, we fed high-fat (HF) and low-fat (LF) pellets. Hepatic TG level was observed in rank order: HF > LF > chow. On both LF and HF, liver TG level was higher in the apob(+/38.9) than in apob(+/+). Hepatic TG secretion remained impaired in the apob(+/38.9) on the HF diet. Thus the FHBL mice are more susceptible to diet-induced fatty liver despite relatively reduced intestinal TG absorption capacity on a HF diet.

Animals↗
PubMed2005

Targeted deletion of the murine apobec-1 complementation factor (acf) gene results in embryonic lethality.

apobec-1 complementation factor (ACF) is an hnRNP family member which functions as the obligate RNA binding subunit of the core enzyme mediating C-to-U editing of the nuclear apolipoprotein B (apoB) transcript. ACF binds to both apoB RNA and apobec-1, the catalytic cytidine deaminase, which then results in site-specific posttranscriptional editing of apoB mRNA. Targeted deletion of apobec1 eliminates C-to-U editing of apoB mRNA but is otherwise well tolerated. However, the functions and potential targets of ACF beyond apoB mRNA editing are unknown. Here we report the results of generating acf knockout mice using homologous recombination. While heterozygous acf(+/)(-) mice were apparently healthy and fertile, no viable acf(-)(/)(-) mice were identified. Mutant acf(-)(/)(-) embryos were detectable only until the blastocyst (embryonic day 3.5 [E3.5]) stage. No acf(-)(/)(-) blastocysts were detectable following implantation at E4.5, and isolated acf(-)(/)(-) blastocysts failed to proliferate in vitro. Small interfering RNA knockdown of ACF in either rat (apobec-1-expressing) or human (apobec-1-deficient) hepatoma cells decreased ACF protein expression and induced a commensurate increase in apoptosis. Taken together, these data suggest that ACF plays a crucial role, which is independent of apobec-1 expression, in cell survival, particularly during early embryonic development.

Animals↗
PubMed2004

Cytidine deamination of retroviral DNA by diverse APOBEC proteins.

The human cytidine deaminase APOBEC3G edits both nascent human immunodeficiency virus (HIV) and murine leukemia virus (MLV) reverse transcripts, resulting in loss of infectivity. The HIV Vif protein is able to protect both viruses from this innate restriction to infection. Here, we demonstrate that a number of other APOBEC family members from both humans and rodents can mediate anti-HIV effects, through cytidine deamination. Three of these, rat APOBEC1, mouse APOBEC3, and human APOBEC3B, are able to inhibit HIV infectivity even in the presence of Vif. Like APOBEC3G, human APOBEC3F preferentially restricts vif-deficient virus. Indeed, the mutation spectra and expression profile found for APOBEC3F indicate that this enzyme, together with APOBEC3G, accounts for the G to A hypermutation of proviruses described in HIV-infected individuals. Surprisingly, although MLV infectivity is acutely reduced by APOBEC3G, no other family member tested here had this effect. It is especially interesting that although both rodent APOBECs markedly diminish wild-type HIV infectivity, MLV is resistant to these proteins. This implies that MLV may have evolved to avoid deamination by mouse APOBEC3. Overall, our findings show that although APOBEC family members are highly related, they exhibit significantly distinct antiviral characteristics that may provide new insights into host-pathogen interactions.

APOBEC-1 Deaminase↗
PubMed2004

Hepatic secretion of small lipoprotein particles in apobec-1-/- mice is regulated by the LDL receptor.

Recent studies have examined the role of the LDL receptor (LDLR) in regulating murine hepatic lipoprotein production and apolipoprotein B (apoB) secretion, with divergent conclusions from in vivo versus in vitro approaches. We have re-examined this question, both in vivo and in vitro, using apobec-1-/- mice to model the pattern of human hepatic apoB-100 secretion. Hepatic triglyceride production in vivo (using Triton WR-1339) was unchanged in wild-type (WT) C57BL/6, apobec-1-/-, ldlr-/-, and [apobec-1-/-, ldlr-/-] mice, while apoB-100 production (using [35S]methionine incorporation) was increased > 2-fold in [apobec-1-/-, ldlr-/-] mice. Although > 90% of newly synthesized apoB floated within the d < 1.006 fraction of serum from all genotypes, fast-performance liquid chromatography separation revealed that nascent triglyceride-rich particles from [apobec-1-/-, ldlr-/-] mice, but not WT, apobec-1-/-, or ldlr-/- mice, distributed into smaller (intermediate and LDL-sized) particles. Studies in isolated hepatocytes from these different genotypes confirmed secretion of smaller particles exclusively from [apobec-1-/-, ldlr-/-] mice, and pulse-chase analysis demonstrated increased secretion of apoB-100 with virtual elimination of posttranslational degradation. These results directly support the suggestion that the LDLR regulates hepatic apoB-100 production and modulates secretion of small, triglyceride-rich particles, both in vivo and in vitro.

APOBEC-1 Deaminase↗
PubMed2004

The peroxisome proliferator-activated receptor alpha (PPARalpha) agonist ciprofibrate inhibits apolipoprotein B mRNA editing in low density lipoprotein receptor-deficient mice: effects on plasma lipoproteins and the development of atherosclerotic lesions.

Low density lipoprotein receptor (LDLR)-deficient mice fed a chow diet have a mild hypercholesterolemia caused by the abnormal accumulation in the plasma of apolipoprotein B (apoB)-100- and apoB-48-carrying intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels. These plasma lipoprotein changes were associated with an increase in the hepatic secretion of apoB-100-carrying very low density lipoproteins (VLDL) and a decrease in the secretion of apoB-48-carrying VLDL, accompanied by a significant decrease in hepatic apoB mRNA editing. Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged. No changes in apoB mRNA editing occurred in the intestine of the treated animals. After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta. These findings demonstrate that ciprofibrate treatment decreases hepatic apoB mRNA editing and alters the pattern of hepatic lipoprotein secretion toward apoB-100-associated VLDL, changes that in turn lead to increased atherosclerosis.

Animals↗
PubMed2004

Detection of murine intestinal adenomas using targeted molecular autofluorescence.

There is a significant need for noninvasive methods of evaluating dysplastic and neoplastic lesions in the luminal gastrointestinal tract. We have optimized an approach based on autofluorescence to study dysplastic adenomatous polyps in Apc(min/+) mice. We made recordings from both normal intestinal mucosa and from polyps using a xenon lamp-based fiberoptic device. Seventy-eight polyps in 11 mice revealed an increase in mean autofluorescence intensity ratios of 1.29 +/- 0.04 (72 small intestinal polyps; P < 0.0001) and 1.28 +/- 0.05 (6 colon polyps; P = 0.0016). Serial measurements of autofluorescence discriminated polyps from normal mucosa with a sensitivity, verified histologically, of 95%. To understand the chemical basis for increased autofluorescence, we examined the tryptophan content of intestinal polyps and the adjacent normal mucosa in a small subset of animals. The findings revealed an increased concentration of tryptophan in polyps (990 +/- 240 ng/mg) compared to normal mucosa (720 +/- 150 ng/mg; P = 0.03). In conclusion, these findings suggest that autofluorescence intensity increases in the setting of intestinal neoplasia and can be used to detect adenomas in the mouse intestine in real time.

Adenomatous Polyps↗
PubMed2004

Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression.

BACKGROUND & AIMS: This study aimed to determine the role of the RNA binding protein apobec-1 in radioprotection of the intestine. METHODS: Apobec-1-deleted mice (APOBEC-1(-/-)) and wild-type controls were treated with 12 Gy of whole-body gamma-irradiation in a cesium irradiator. The number of surviving intestinal crypts was assessed 3.5 days after irradiation by using a clonogenic assay. Cyclooxygenase-2 messenger RNA and protein expression were determined by real-time polymerase chain reaction and Western blot, respectively. RNA stability was studied by examining the turnover of a chimeric transcript containing the cyclooxygenase-2 3' untranslated region cloned downstream of luciferase complementary DNA. Apobec-1 binding to the cyclooxygenase-2 3' untranslated region was studied by electrophoretic mobility shift and UV crosslinking assays. RESULTS: After gamma-irradiation, the survival of intestinal stem cells decreased significantly in APOBEC-1(-/-) mice. In wild-type mice treated with lipopolysaccharide before gamma-irradiation, intestinal stem cells were protected by marked increases in prostaglandin E 2 mediated by cyclooxygenase-2. No such effect was observed in the APOBEC-1(-/-) mice. The mechanism of this radioprotective effect involves the binding of apobec-1 to AU-rich sequences in the first 60 nucleotides of the 3' untranslated region of cyclooxygenase-2. Upon binding to the AU-rich sequences, apobec-1 stabilizes cyclooxygenase-2 messenger RNA. This stabilization process does not seem to be mediated by p38 mitogen-activated protein kinase pathways. CONCLUSIONS: Lipopolysaccharide increases intestinal stem cell survival through apobec-1-mediated regulation of cyclooxygenase-2 messenger RNA stability.

3' Untranslated Regions↗
PubMed2004

Inhibition of Hedgehog signaling protects adult mice from diet-induced weight gain.

Hedgehog (Hh) signaling plays an important role in embryonic development of many tissues, including the gastrointestinal tract. Sonic Hh-and Indian Hh-deficient mice die before or soon after birth, precluding further study of this signaling pathway in the mature intestine. Maternal transfer of inactivating monoclonal antibodies to Hh proteins (anti-Hh moAb) during late stages of embryogenesis or to early postnatal mice produced intestinal villous abnormalities, progressive runting, and severe malabsorption of dietary fat. In the present study, we sought to determine the effect of inhibiting Hh signaling on weight gain and lipid absorption in adult mice. Anti-Hh moAb was administered to adult Balb/c mice fed either a low-fat, nonpurified diet or a high-fat, semipurified diet, and to adult ob/ob mice fed the low-fat, nonpurified diet. Weight gain was significantly inhibited by anti-Hh moAb treatment in Balb/C mice fed the high-fat, but not the low-fat diet and in ob/ob mice. Further analysis of adult Balb/c mice fed the high-fat diet demonstrated that although total lipid absorption was normal, the rate of triglyceride absorption was significantly delayed in mice treated with anti-Hh moAb and they had significantly increased fecal FFA excretion. Hepatic steatosis, found in high-fat fed Balb/c mice treated with the control moAb, was abrogated by anti-Hh moAb administration. These findings point to a potential role for Hh signaling pathways in diet-induced abnormalities of lipid metabolism.

Animals↗