Genetic and hormonal control of hepatic steatosis in female and male mice (original) (raw)
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Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice
International Journal of Molecular Sciences
Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex...
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018
The present study was planned to improve our understanding about sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice. Female (FCaf) and male (MCaf) mice fed a cafeteria diet had similar body weight gain and adiposity index, but FCaf had a more extensive steatosis than MCaf. FCaf livers exhibited a higher non-alcoholic fatty liver disease activity score, elevated lipid percentage area (+34%) in Sudan III staining and increased TG content (+25%) compared to MCaf. Steatosis in FCaf was not correlated with changes in the transcript levels of lipid metabolism-related genes, but a reduced VLDL release rate was observed. Signs of oxidative stress were found in FCaf livers, as elevated malondialdehyde content (+110%), reduced catalase activity (-36%) and increased Nrf2 and Hif1a mRNA expression compared to MCaf. Interestingly, fibroblast growth factor 21 (Fgf21) mRNA expression was found to be exclusively induced in MCaf, which also exhibited higher FGF21 serum levels (+416%) and hepatic protein abundance (+163%) than FCaf. Moreover, cafeteria diet increased Fgfr1, Fsp27 and Ucp1 mRNA expression in brown adipose tissue of males (MCaf), but not females (FCaf). FGF21 hepatic production by male mice seems to be part of a complex network of responses to the nutritional stress of the cafeteria diet, probably related to the unfolded protein response activation. Although aimed at the restoration of hepatic metabolic homeostasis, the branch involving Fgf21 upregulation seems to be impaired in females, rendering them incapable of reducing the hepatic lipid content and cellular oxidative stress.
Mapping liver fat female-dependent quantitative trait loci in collaborative cross mice
Mammalian genome : official journal of the International Mammalian Genome Society, 2016
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the western world, with spectrum from simple steatosis to non-alcoholic steatohepatitis, which can progress to cirrhosis. NAFLD developments are known to be affected by host genetic background. Herein we emphasize the power of collaborative cross (CC) mouse for dissecting this complex trait and revealing quantitative trait loci (QTL) controlling hepatic fat accumulation in mice. 168 female and 338 male mice from 24 and 37 CC lines, respectively, of 18-20 weeks old, maintained on standard rodent diet, since weaning. Hepatic fat content was assessed, using dual DEXA scan in the liver. Using the available high-density genotype markers of the CC line, QTL mapping associated with percentage liver fat accumulation was performed. Our results revealed significant fatty liver accumulation QTL that were specifically, mapped in females. Two significant QTLs on chromosomes 17 and 18, with genomic inte...
Liver fatty acid composition correlates with body fat and sex in a multigenic mouse model of obesity
The American journal of clinical nutrition, 1994
To determine whether there is altered liver lipid-fraction fatty acid distribution in a multigenic obese mouse model, we examined livers from eight lean (0.2-4.2% carcass fat), seven intermediate (5.7-13.8%), and five obese (20.2-48.7%) backcross progeny [(C57BL/6J x Mus spretus) x C57BL/6J] aged 2-3 mo. Thirteen males and seven females were fed a nonpurified stock diet. Liver lipid fractions were separated and fatty acids quantitated by thin-layer and gas chromatography. There was a significant effect of obesity on 18:2 omega 6 in liver phospholipids (PL), cholesteryl esters, and triglycerides. PL 18:2 omega 6 was negatively correlated with carcass fat (r = -0.74, P < 0.001); 20:3 omega 6 was elevated in PL with increased obesity (P < 0.0001), and was correlated with carcass fat (r = 0.92, P < 0.0001); and 20:4 omega 6 in PL did not differ with obesity status. PL 20:3 omega 6 and 20:4 omega 6 were lower in males (P < 0.01 and 0.02, respectively) than in females. We conc...
Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice
NMR in biomedicine, 2017
Ectopic lipid accumulation in the liver is implicated in metabolic disease in an age- and sex-dependent manner. The role of hepatic lipids has been well established within the scope of metabolic insults in mice, but has been insufficiently characterized under standard housing conditions, where age-related metabolic alterations are known to occur. We studied a total of 10 male and 10 female mice longitudinally. At 3, 7 and 11 months of age, non-invasive (1) H-magnetic resonance spectroscopy ((1) H-MRS) was used to monitor hepatic lipid content (HLC) and fatty acid composition in vivo, and glucose homeostasis was assessed with glucose and insulin challenges. At the end of the study, hepatic lipids were comprehensively characterized by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometric analyses of liver tissue samples. In males, HLC increased from 1.4 ± 0.1% at 3 months to 2.9 ± 0.3% at 7 months (p < 0.01) and 2.7 ± 0.3% at 11 months (p < 0.05), in corr...
Quantitative Trait Loci Affecting Liver Fat Content in Mice
G3: Genes|Genomes|Genetics, 2012
Nonalcoholic fatty liver disease, a condition in which excess fat accumulates in the liver, is strongly associated with the metabolic syndrome, including obesity and other related conditions. This disease has the potential to progress from steatosis to steatohepatitis, fibrosis, and cirrhosis. The recent increase in the prevalence of the metabolic syndrome is largely driven by changes in diet and activity levels. Individual variation in the response to this obesogenic environment, however, is attributable in part to genetic variation between individuals, but very few mammalian genetic loci have been identified with effects on fat accumulation in the liver. To study the genetic basis for variation in liver fat content in response to dietary fat, liver fat proportion was determined using quantitative magnetic resonance imaging in 478 mice from 16 LG/J X SM/J recombinant inbred strains fed either a high-fat (42% kcal from fat) or lowfat (15% kcal from fat) diet. An analysis of variance confirmed that there is a genetic basis for variation in liver fat content within the population with significant effects of sex and diet. Three quantitative trail loci that contribute to liver fat content also were mapped. KEYWORDS nonalcoholic fatty liver disease NAFLD QTL mouse LG/J SM/J Atzmon et al. 2002; Wajchenberg et al. 2002). Fabbrini et al.
Age-dependent sex difference of non-alcoholic fatty liver disease in TSOD and db/db mice
PLOS ONE, 2022
According to previous clinical studies, the prevalence of non-alcoholic fatty liver disease (NAFLD) is higher in men than women only during the reproductive age. Animal models of NAFLD that reflect sex differences in humans have not been established. In this study, we examined sex differences in the hepatic lesions of Tsumura Suzuki obese diabetes (TSOD) and db/db mice, which are representative genetic models of NAFLD. Male and female TSOD and db/db mice were fed with a normal diet and tap water ad libitum. Six male and female mice of each strain were sacrificed at the ages of 3 and 9 months, respectively, and serum biochemical, pathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) levels were significantly higher in male than female mice of both strains at the age of 3 months; however, at 9 months, significant sex differences were not observed. Similarly, alanine aminotransferase (ALT) levels were significantly higher in male mice than in female TSOD mice at the age of 3 months; however, at 9 months, significant sex differences were not observed. Image analysis of histological slides revealed that the frequency of the steatotic area was significantly higher in male than female db/db mice at the age of 3 months; however, significant sex differences were not observed at 9 months. The frequency of Sirius red-positive fibrotic area was significantly higher in male than female mice in both strains at the age of 3 months; however, significant sex differences were not observed at 9 months. Serum AST and ALT levels and hepatic steatosis and fibrosis in TSOD and db/db mice showed age-dependent sex differences consistent with those observed in human NAFLD. These mice may be suitable for studying sex differences of the disease.
Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice
International Journal of Obesity, 2017
BACKGROUND-Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and NAFLD but estrogen has undesirable side effects which negate its beneficial effects in pre-and post-menopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. ERα is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: 1) inducing gene transcription by direct binding to specific DNA sequences 2) inducing tethered transcription with other DNA binding factors 3) stimulating nongenomic action through membrane associated ERα. However, it is still unclear which mechanisms mediate ERα dependent protection against hepatic steatosis. METHODS-To understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA binding domain mutant mouse (KIKO), and liver-specific ERα knockout mouse (LERKO) fed high fat diets (HFD). The KIKO mouse disrupts the direct DNA binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum ALT levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis. RESULTS-Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed WT controls. Conversely, HFD-fed LERKO females did not accumulate excess liver Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The Effects of Sex and Diet on Physiology and Liver Gene Expression in Diversity Outbred Mice
2017
Inter-individual variation in metabolic health and adiposity is driven by many factors. Diet composition and genetic background and the interactions between these two factors affect adiposity and related traits such as circulating cholesterol levels. In this study, we fed 850 Diversity Outbred mice, half females and half males, with either a standard chow diet or a high fat, high sucrose diet beginning at weaning and aged them to 26 weeks. We measured clinical chemistry and body composition at early and late time points during the study, and liver transcription at euthanasia. Males weighed more than females and mice on a high fat diet generally weighed more than those on chow. Many traits showed sex- or diet-specific changes as well as more complex sex by diet interactions. We mapped both the physiological and molecular traits and found that the genetic architecture of the physiological traits is complex, with many single locus associations potentially being driven by more than one ...