Genetic, epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/J×SM/J murine model

Lawson, Heather A.; Zelle, Kathleen M.; Fawcett, Gloria L.; Wang, Bing; Pletscher, L. Susan; Maxwell, Taylor J.; Ehrich, Thomas H.; Kenney-Hunt, Jane P.; Wolf, Jason B.; Semenkovich, Clay F.; Cheverud, James M.

doi:10.1194/jlr.m006957

Cited by 33 publications

(42 citation statements)

References 54 publications

(49 reference statements)

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“…A quantitative trait locus (QTL) associated with variation in serum triglyceride levels was mapped to chromosome 7 (chr7: 100,028,746 – 105,636,301; GRCm38/mm10) in an F 16 generation (n=1002) of an advanced intercross between the LG/J and SM/J inbred mouse strains (18), which have proven to be useful for genetic analysis of metabolic traits. The QTL interval overlaps an olfactory receptor cluster and contains 272 genes, of which 85 are protein coding.…”

Section: Resultsmentioning

confidence: 99%

“…In a QTL associated with variation in serum triglycerides, Dserum7b , mapped in the F 16 generation of a LG/J × SM/J advanced intercross mouse population (18), Hpx emerged as a promising candidate gene. There are 5 small deletion polymorphisms in the SM/J founder strain relative to the LG/J founder strain in the Hpx genic region (Supplementary Table 4).…”

Section: Discussionmentioning

confidence: 99%

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Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

et al. 2017

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Background/Objectives Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects. Subjects/Methods Hemopexin was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both reproductive fatpads and livers of mice representing three strains, LG/J (n = 25), SM/J (n = 27) and C57Bl/6J (n = 19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n = 18) and of metabolically normal (n = 24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n = 18). Results Hemopexin expression in mouse adipose tissue, but not liver, was regulated by dietary fat regardless of genetic background. Hemopexin increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of hemopexin based on metabolic disease status (p < 0.05), and circulating hemopexin levels were correlated with serum triglycerides in these subjects (r = 0.33; p = 0.03). Hemopexin was also found in an unbiased proteomic screen of human atherosclerotic plaques, and shown to display differential abundance based on extent of disease and triglyceride content (p < 0.05). Conclusions Our findings suggest that hemopexin is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

et al. 2017

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“…Concerning TLR2 promoter, additional chromatin modification such as hyperlipidemic lipoprotein-associated aberrant DNA methylation (30) may have interfered with histone acetylation, thereby impairing the recovery of TLR2 expression. The impaired histone acetylation in DIO mice might result from FFA-and TNF-induced epigenetic changes on gene promoters causing a low NF-κB binding to gene promoters (31).…”

Section: Discussionmentioning

confidence: 99%

Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

Zhou¹,

Leeman

Amar³

2011

Proc. Natl. Acad. Sci. U.S.A.

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Our previous data have linked obesity with immune dysfunction. It is known that physical exercise with dietary control has beneficial effects on immune function and the comorbidities of obesity. However, the mechanisms underlying the improvement of immune function in obesity after physical exercise with dietary control remain unknown. Here we show that moderate daily exercise with dietary control restores the impaired cytokine responses in dietinduced obese (DIO) mice and improves the resolution of Porphyromonas gingivalis-induced periodontitis. This restoration of immune responses is related to the reduction of circulating free fatty acids (FFAs) and TNF. Both FFAs and TNF induce an Akt inhibitor, carboxylterminal modulator protein (CTMP). The expression of CTMP is also observed increased in bone marrow-derived macrophages (BMMΦ) from DIO mice and restored after moderate daily exercise with dietary control. Toll-like receptor 2 (TLR2), which increases CTMP induction by FFAs, is inhibited in BMMΦ from DIO mice or after either FFA or TNF treatment, but unexpectedly is not restored by moderate daily exercise with dietary control. Furthermore, BMMΦ from DIO mice display reduced histone H3 (Lys-9) acetylation and NF-κB recruitment to TNF, IL-10, and TLR2 promoters after P. gingivalis infection. However, moderate daily exercise with dietary control restores these defects at promoters for TNF and IL-10, but not for TLR2. Thus, metabolizing FFAs and TNF by moderate daily exercise with dietary control improves innate immune responses to infection in DIO mice via restoration of CTMP and chromatin modification.innate immunity | bacteria clearance | Akt pathway E xcessive energy intake and sedentariness are prominent risk factors for becoming overweight and developing obesity (1, 2). Obesity is a predisposing risk factor for many health problems, including hypertension, dyslipidemia, atherosclerosis, diabetes, nonalcoholic fatty liver disease, periodontal disease, certain cancers, and asthma (3-6). Changes in immune functions have been proposed as underlying the pathogenesis of all these diseases. Obesity induces immune defects that lead to attenuated host responses to infection (7-9). The combination of dietary and exercise interventions has been proved to provide the most beneficial effects to obese people (10-12). However, few studies have addressed the molecular mechanisms involved in the restoration of obesity-induced immune defects.We previously demonstrated that diet-induced obesity (DIO) inhibited the ability of the immune system to appropriately respond to Porphyromonas gingivalis infection and concluded that this immune dysregulation participated in the increased alveolar bone loss from bacterial infections observed in DIO mice (7). Both free fatty acids (FFAs) and TNF are elevated in obesity and are important parameters for the comorbidities of obesity (13-16). FFAs activate toll-like receptor 4 (TLR4)-mediated inflammatory signaling pathways and induce TNF expression in DIO mice (16).In contrast, TLR2, which ne...

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“…A difference in expression in Lipg explained the chromosome 18 HDL QTL in at least three mouse crosses (B6×D2, NZB×SM, B6×C3H) ( 26 ). However, we identifi ed a novel nonsynonymous coding polymorphism that is probably responsible for the chromosome 18 QTL in the MRL×SM cross as well as the differences between the SM×NZB ( 35 ) and LG×SM crosses ( 30 ). In addition, although our approach is a powerful way to identify potential QTL candidate genes, our study refl ects the complexity of the identifi cation of QTL genes.…”

Section: Discussionmentioning

confidence: 85%

Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ × SM/J intercross

Leduc

Blair

Verdugo

et al. 2012

Journal of Lipid Research

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A higher incidence of coronary artery disease (CAD) is associated with a lower level of HDL-cholesterol ( 1, 2 ), which is determined by multiple environmental and genetic factors. In the past few years, new therapeutic approaches have focused on fi nding ways to increase HDL ( 3, 4 ). To date, however, only a few environmental interventions, such as diet and exercise, have been successful in raising HDL level ( 5 ), whereas drug therapy development is still ongoing and has targeted only a limited number of proteins such as CETP ( 3, 4 ). In the search for a potential drug target to raise HDL and decrease CAD, the identifi cation of new genes involved in HDL determination is essential.The genetic basis of HDL-cholesterol variation has been widely studied in various animal models. In humans, recent genome-wide association studies (GWAS) have identifi ed known HDL genes such as LIPG and CETP in addition to new genes such as GALNT2 ( 6 ). These known genes, however, explain only a small proportion of the total variation, indicating that additional genes are yet to be discovered. Mouse models are a powerful strategy for identifying such genes. A large overlap exists among species for quantitative trait loci (QTL) and genes involved in lipid metabolism ( 7 ). Many study methodologies are similar between human and mouse, but mouse studies offer advantages by capitalizing on genomics tools that are not available and practical for studies of human populations. To date, our laboratory and those of others have identifi ed over 35 mouse HDL QTL (as reviewed in Wang et al., Refs. 7,8 ). In addition, we and others have developed bioinformatics tools to narrow the QTL interval to just a few candidate genes ( 9, 10 ). Application of these tools has led to the discovery of single genes underlying QTL for HDL and

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Genetic, epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/J×SM/J murine model

Cited by 33 publications

References 54 publications

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ × SM/J intercross

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