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1.  Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance 
Cell metabolism  2013;18(1):106-117.
Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXR signaling is required for key aspects of the metabolic syndrome in obese mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese, but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects of LXR on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in beta-cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into complex relationships between LXR and insulin signaling.
PMCID: PMC4089509  PMID: 23823481
Nuclear receptor; liver X receptor (LXR); peroxisome proliferator-activated receptor (PPAR); carbohydrate response element binding protein (ChREBP); insulin resistance; diabetes; obesity; metabolic syndrome; hepatic steatosis; insulin signaling
2.  Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits 
We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5 % of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.
PMCID: PMC3586763  PMID: 22892838
3.  The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice 
PLoS Genetics  2012;8(5):e1002709.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
Author Summary
Differences exist between men and women in the development of obesity and related metabolic diseases such as type 2 diabetes and cardiovascular disease. Previous studies have focused on the sex-biasing role of hormones produced by male and female gonads, but these cannot account fully for the sex differences in metabolism. We discovered that removal of the gonads uncovers an important genetic determinant of sex differences in obesity—the presence of XX or XY sex chromosomes. We used a novel mouse model to tease apart the effects of male and female gonads from the effects of XX or XY chromosomes. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had increased body fat and ate more food during the sleep period. Mice with two X chromosomes also had accelerated weight gain, fatty liver, and hyperinsulinemia on a high fat diet. The higher expression levels of a subset of genes on the X chromosome that escape inactivation may influence adiposity and metabolic disease. The effect of X chromosome genes is present throughout life, but may become particularly significant with increases in longevity and extension of the period spent with reduced gonadal hormone levels.
PMCID: PMC3349739  PMID: 22589744
4.  Liver X Receptor Signaling is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease 
Gastroenterology  2010;140(3):1052-1062.
Background & Aims
Liver X receptors (LXRs) are lipid-activated nuclear receptors with important roles in cholesterol transport, lipogenesis, and anti-inflammatory signaling. Hepatic stellate cells (HSCs) activate during chronic liver injury and mediate the fibrotic response. These cells are also major repositories for lipids, but the role of lipid metabolism during stellate cell activation remains unclear. Here we show that LXR signaling is an important determinant of stellate cell activation and susceptibility to fibrotic liver disease.
Immortalized and primary stellate cells purified from mice were treated with highly specific LXR ligands. Carbon tetrachloride (CCl4) and methionine choline deficiency (MCD) were used as chronic liver injury models. Reciprocal bone marrow transplants were performed to test the importance of hematopoietically-derived cells to the fibrotic response.
LXR ligands suppressed markers of fibrosis and stellate cell activation in primary mouse stellate cells. Lxrαβ −/− stellate cells produce increased levels of inflammatory mediators and conditioned media from Lxrαβ−/− cells increases the fibrogenic program of wild-type cells. Furthermore, Lxrαβ−/− stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxrαβ−/− mice have marked susceptibility to fibrosis in two injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxrαβ−/− phenotype.
These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.
PMCID: PMC3049833  PMID: 21134374
Nuclear receptors; LXRs; hepatic stellate cells; liver fibrosis
5.  Coordinate regulation of neutrophil homeostasis by liver X receptors in mice 
The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 109 neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop have remained indeterminate. Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate both lipid metabolic and inflammatory gene expression. Here, we demonstrate that LXRs contribute to the control of neutrophil homeostasis. Using gain- and loss-of-function models, we found that LXR signaling regulated the efficient clearance of senescent neutrophils by peripheral tissue APCs in a Mer-dependent manner. Furthermore, activation of LXR by engulfed neutrophils directly repressed the IL-23/IL-17/G-CSF granulopoietic cytokine cascade. These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression.
PMCID: PMC3248291  PMID: 22156197

Results 1-5 (5)