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Ding L, Liu J, Zhou L, Zhang Q, Liu J, Xiao X. Maternal high-fat diet alters the transcriptional rhythm in white adipose tissue of adult offspring. J Nutr Biochem 2025; 138:109843. [PMID: 39826765 DOI: 10.1016/j.jnutbio.2025.109843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 01/11/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
A maternal high-fat diet (HFD) deteriorates the long-term metabolic health of offspring. Circadian rhythms are crucial for regulating metabolism. However, the impact of maternal HFD on the circadian clock in white adipose tissue (WAT) remains unexplored. This study aimed to identify transcriptional rhythmic alterations in inguinal WAT of adult male offspring induced by maternal HFD. To this end, female mice were fed an HFD and their male offspring were raised on a standard chow diet until 16 weeks of age. Transcriptome was performed and the data was analyzed using CircaCompare. The results showed that maternal HFD before and throughout pregnancy significantly altered the circadian rhythm of inguinal WAT while slightly modifying the WAT clock in adult male offspring. Specifically, maternal HFD contributed to gaining rhythmicity of Cry2, resulted in the elevated amplitude of Nr1d2, and led to increased midline estimating statistic of rhythm (MESOR) of Clock and Nr1d2. Furthermore, maternal HFD changed the rhythmic pattern of metabolic genes, such as Pparγ, Hacd2, and Acsl1, which are significantly enriched in metabolic regulation pathways. In conclusion, a maternal HFD before and throughout pregnancy altered the circadian rhythm of inguinal WAT in adult offspring. These alterations may play a significant role in disturbing metabolic homeostasis, potentially leading to metabolic dysfunction in adult male offspring.
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Affiliation(s)
- Lu Ding
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing Liu
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Liyuan Zhou
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Qian Zhang
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jieying Liu
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Xinhua Xiao
- Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Schaeffer S, Bogdanovic A, Hildebrandt T, Flint E, Geng A, Pecenko S, Lussier P, Strumberger MA, Meyer M, Weber J, Heim MH, Cajochen C, Bernsmeier C. Significant nocturnal wakefulness after sleep onset in metabolic dysfunction-associated steatotic liver disease. FRONTIERS IN NETWORK PHYSIOLOGY 2024; 4:1458665. [PMID: 39698501 PMCID: PMC11652136 DOI: 10.3389/fnetp.2024.1458665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/30/2024] [Indexed: 12/20/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystemic disease with a multifactorial pathogenesis involving dietary, environmental, and genetic factors. Previous mouse models suggested that circadian misalignment may additionally influence its development as it influences metabolism in diverse organs including the liver. Further, data from sleep questionnaires proved sleep-wake disruption in patients with MASLD. We objectively assessed sleep-wake rhythms in patients with biopsy-proven MASLD (n = 35) and healthy controls (HC, n = 16) using actigraphy 24/7 for 4 weeks. With the aim to re-align sleep rhythms a single standardized sleep hygiene education session was performed after 2 weeks. Actigraphy data revealed that MASLD patients had more awakenings per night (MASLD vs. HC 8.5 vs. 5.5, p = 0.0036), longer wakefulness after sleep onset (MASLD vs. HC 45.4 min vs. 21.3 min, p = 0.0004), and decreased sleep efficiency (MASLD vs. HC 86.5% vs. 92.8%, p = 0.0008) compared with HC despite comparable sleep duration. Patients with MASLD self-reported shorter sleep duration (MASLD vs. HC 6 h vs. 6 h 45 min, p = 0.01) and prolonged sleep latency contributing to poorer sleep quality. Standardized sleep hygiene education did not produce significant changes in sleep parameters. Our findings indicate fragmented nocturnal sleep in patients with MASLD, characterized by increased wakefulness and reduced sleep efficiency, perceived subjectively as shortened sleep duration and delayed onset. A single sleep hygiene education session did not improve sleep parameters.
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Affiliation(s)
- Sofia Schaeffer
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
- University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Andrijana Bogdanovic
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Talitha Hildebrandt
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Emilio Flint
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Anne Geng
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Sylvia Pecenko
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Paul Lussier
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Michael A. Strumberger
- Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland
| | - Martin Meyer
- Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland
| | | | - Markus H. Heim
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
- University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Christian Cajochen
- Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland
| | - Christine Bernsmeier
- Department of Biomedicine and Department of Clinical Research, University of Basel, Basel, Switzerland
- University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
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3
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Mouzaki M, Woo JG, Divanovic S. Gestational and Developmental Contributors of Pediatric MASLD. Semin Liver Dis 2024; 44:43-53. [PMID: 38423068 DOI: 10.1055/s-0044-1782210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is common and can be seen as early as in utero. A growing body of literature suggests that gestational and early life exposures modify the risk of MASLD development in children. These include maternal risk factors, such as poor cardiometabolic health (e.g., obesity, gestational diabetes, rapid weight gain during pregnancy, and MASLD), as well as periconceptional dietary exposures, degree of physical activity, intestinal microbiome, and smoking. Paternal factors, such as diet and obesity, also appear to play a role. Beyond gestation, early life dietary exposures, as well as the rate of infant weight gain, may further modify the risk of future MASLD development. The mechanisms linking parental health and environmental exposures to pediatric MASLD are complex and not entirely understood. In conclusion, investigating gestational and developmental contributors to MASLD is critical and may identify future interventional targets for disease prevention.
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Affiliation(s)
- Marialena Mouzaki
- Divisions of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jessica G Woo
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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4
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Chen Z, Xia LP, Shen L, Xu D, Guo Y, Wang H. Glucocorticoids and intrauterine programming of nonalcoholic fatty liver disease. Metabolism 2024; 150:155713. [PMID: 37914025 DOI: 10.1016/j.metabol.2023.155713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/17/2023] [Accepted: 10/20/2023] [Indexed: 11/03/2023]
Abstract
Accumulating epidemiological and experimental evidence indicates that nonalcoholic fatty liver disease (NAFLD) has an intrauterine origin. Fetuses exposed to adverse prenatal environments (e.g., maternal malnutrition and xenobiotic exposure) are more susceptible to developing NAFLD after birth. Glucocorticoids are crucial triggers of the developmental programming of fetal-origin diseases. Adverse intrauterine environments often lead to fetal overexposure to maternally derived glucocorticoids, which can program fetal hepatic lipid metabolism through epigenetic modifications. Adverse intrauterine environments program the offspring's glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis, which contributes to postnatal catch-up growth and disturbs glucose and lipid metabolism. These glucocorticoid-driven programming alterations increase susceptibility to NAFLD in the offspring. Notably, after delivery, offspring often face an environment distinct from their in utero life. The mismatch between the intrauterine and postnatal environments can serve as a postnatal hit that further disturbs the programmed endocrine axes, accelerating the onset of NAFLD. In this review, we summarize the current epidemiological and experimental evidence demonstrating that NAFLD has an intrauterine origin and discuss the underlying intrauterine programming mechanisms, focusing on the role of overexposure to maternally derived glucocorticoids. We also briefly discuss potential early life interventions that may be beneficial against fetal-originated NAFLD.
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Affiliation(s)
- Ze Chen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, China
| | - Li-Ping Xia
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Lang Shen
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Dan Xu
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China; Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Yu Guo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
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5
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Chiodi V, Rappa F, Lo Re O, Chaldakov GN, Lelouvier B, Micale V, Domenici MR, Vinciguerra M. Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice. Sci Rep 2023; 13:19123. [PMID: 37926763 PMCID: PMC10625986 DOI: 10.1038/s41598-023-46304-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023] Open
Abstract
Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and females.
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Affiliation(s)
- Valentina Chiodi
- National Centre for Drug Research and Evaluation, Istituto Superiore di Sanita', Rome, Italy
| | - Francesca Rappa
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, Palermo, Italy
| | - Oriana Lo Re
- Department of Translational Stem Cell Biology, Research Institute of the Medical University, Varna, Bulgaria
- International Clinical Research Center (FNUSA-ICRC), St'Anne University Hospital, Brno, Czech Republic
| | - George N Chaldakov
- Department of Translational Stem Cell Biology, Research Institute of the Medical University, Varna, Bulgaria
- Department of Anatomy and Cell Biology, Research Institute of the Medical University, Varna, Bulgaria
| | | | - Vincenzo Micale
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
| | - Maria Rosaria Domenici
- National Centre for Drug Research and Evaluation, Istituto Superiore di Sanita', Rome, Italy
| | - Manlio Vinciguerra
- Department of Translational Stem Cell Biology, Research Institute of the Medical University, Varna, Bulgaria.
- International Clinical Research Center (FNUSA-ICRC), St'Anne University Hospital, Brno, Czech Republic.
- Liverpool Centre for Cardiovascular Science (LCCS), Liverpool John Moores University, Liverpool, UK.
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Lapa Neto CJC, de Melo IMF, Alpiovezza PKBM, de Albuquerque YML, Francisco Soares A, Teixeira ÁAC, Wanderley-Teixeira V. Melatonin associated with a high-fat diet during pregnancy and lactation prevents liver changes in the offspring. Gen Comp Endocrinol 2023; 343:114357. [PMID: 37586542 DOI: 10.1016/j.ygcen.2023.114357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/07/2023] [Indexed: 08/18/2023]
Abstract
In the present study, we set out to determine whether melatonin combined with a high-fat diet during pregnancy and lactation can prevent liver disorders in offspring. Forty rats were divided into four groups: DC - pregnant rats submitted to the standard diet; DC + Mel - pregnant rats submitted to the standard diet combined with melatonin; HFD - pregnant rats submitted to a high-fat diet; HFD + Mel - pregnant rats submitted to a high-fat diet combined with melatonin. Morphophysiological and biochemical parameters were analyzed. Melatonin (5 mg/kg) was administered intraperitoneally. The HFD group offspring showed an increase in AST, ALT, alkaline phosphatase, cholesterol, triglycerides, LDL and glucose levels, and a reduction in HDL and lipase levels. In the liver obseved steatosis, hepatocellular ballooning, increased lobular parenchyma and reduced non-lobular parenchyma, beside reduced liver glycogen and fibrosis. These changes were not observed in the HFD + Mel group. In conclusion, melatonin combined with a high-fat diet preserves the liver architecture and function in the offspring.
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Affiliation(s)
- Clovis J C Lapa Neto
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Ismaela M F de Melo
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Paloma K B M Alpiovezza
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Yuri M L de Albuquerque
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Anísio Francisco Soares
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Álvaro A C Teixeira
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil
| | - Valéria Wanderley-Teixeira
- Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife, PE, Brazil.
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7
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Neto JGO, Woyames J, Andrade CBV, de Almeida MM, Fassarella LB, Atella GC, Takyia CM, Trevenzoli IH, Pazos-Moura CC. Effect of Gestational Fish Oil Supplementation on Liver Metabolism and Mitochondria of Male and Female Rat Offspring Programmed by Maternal High-Fat Diet. Mol Nutr Food Res 2023; 67:e2200479. [PMID: 36782400 DOI: 10.1002/mnfr.202200479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/20/2023] [Indexed: 02/15/2023]
Abstract
SCOPE Perinatal maternal moderately high-fat diet (mHFD) is associated with obesity and fatty liver disease in offspring, and maternal fish oil (FO: n-3 PUFA source) supplementation may attenuate these disorders. This study evaluates the effects of FO given to pregnant rats fed a mHFD on the offspring's liver at weaning. METHODS AND RESULTS Female Wistar rats receive an isoenergetic, control (CT: 10.9% from fat) or high-fat (HF: 28.7% from fat) diet before mating, and throughout pregnancy and lactation. FO supplementation (HFFO: 2.9% of FO in the HF diet) is given to one subgroup of HF dams during pregnancy. At weaning, male and female mHFD offspring display higher body mass, adiposity, and hepatic cellular damage, steatosis, and inflammation, accompanied by increased damaged mitochondria. FO does not protect pups from systemic metabolic alterations and partially mitigates hepatic histological damage induced by mHFD only in females. However, FO reduces mRNA expression of lipogenic genes, and mitochondrial damage, and modified mitochondrial morphology suggestive of early adaptations via mitochondrial dynamics. CONCLUSIONS Gestational FO supplementation has limited beneficial effects on the damage caused by perinatal mHFD consumption in offspring's liver at weaning. However, FO imprinting effect on lipid metabolism and mitochondria may have beneficial long-term outcomes.
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Affiliation(s)
| | - Juliana Woyames
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Cherley Borba Vieira Andrade
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Mariana Macedo de Almeida
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Larissa Brito Fassarella
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Georgia Correia Atella
- Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Christina Maeda Takyia
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Isis Hara Trevenzoli
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
| | - Carmen Cabanelas Pazos-Moura
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil
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Galvan-Martinez DH, Bosquez-Mendoza VM, Ruiz-Noa Y, Ibarra-Reynoso LDR, Barbosa-Sabanero G, Lazo-de-la-Vega-Monroy ML. Nutritional, pharmacological, and environmental programming of NAFLD in early life. Am J Physiol Gastrointest Liver Physiol 2023; 324:G99-G114. [PMID: 36472341 DOI: 10.1152/ajpgi.00168.2022] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.
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Affiliation(s)
| | | | - Yeniley Ruiz-Noa
- Health Sciences Division, Medical Sciences Department, University of Guanajuato, Campus Leon, Mexico
| | | | - Gloria Barbosa-Sabanero
- Health Sciences Division, Medical Sciences Department, University of Guanajuato, Campus Leon, Mexico
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9
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Human centenarian-associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids. GeroScience 2022; 45:1177-1196. [PMID: 36534275 PMCID: PMC9886743 DOI: 10.1007/s11357-022-00713-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.
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10
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Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Gastroenterol 2022; 28:2890-2899. [PMID: 35978876 PMCID: PMC9280730 DOI: 10.3748/wjg.v28.i25.2890] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/20/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.
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Affiliation(s)
- Natalia Balassiano Wajsbrot
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Nathalie Carvalho Leite
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Gil F Salles
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
| | - Cristiane A Villela-Nogueira
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
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11
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Xiang J, Deng YY, Liu HX, Pu Y. LncRNA MALAT1 Promotes PPARα/CD36-Mediated Hepatic Lipogenesis in Nonalcoholic Fatty Liver Disease by Modulating miR-206/ARNT Axis. Front Bioeng Biotechnol 2022; 10:858558. [PMID: 35769097 PMCID: PMC9234139 DOI: 10.3389/fbioe.2022.858558] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are known to play crucial roles in nonalcoholic fatty liver disease (NAFLD). This research sought to explore mechanisms by which lncRNA MALAT1 regulates the progression of NAFLD. Thus, in order to detect the function of MALAT1 in NAFLD, in vitro and in vivo model of NAFLD were established. Then, fatty acid uptake and triglyceride level were investigated by BODIPY labeled-fatty acid uptake assay and Oil red O staining, respectively. The expressions of MALAT1, miR-206, ARNT, PPARα and CD36 were detected by western blotting and qPCR. Dual luciferase, RIP and ChIP assay were used to validate the relation among MALAT1, miR-206, ARNT and PPARα. The data revealed expression of MALAT1 was up-regulated in vitro and in vivo in NAFLD, and knockdown of MALAT1 suppressed FFA-induced lipid accumulation in hepatocytes. Meanwhile, MALAT1 upregulated the expression of ARNT through binding with miR-206. Moreover, miR-206 inhibitor reversed MALAT1 knockdown effects in decreased lipid accumulation in FFA-treated hepatocytes. Furthermore, ARNT could inhibit the expression of PPARα via binding with PPARα promoter. Knockdown of MALAT1 significantly upregulated the level of PPARα and downregulated the expression of CD36, while PPARα knockdown reversed these phenomena. MALAT1 regulated PPARα/CD36 -mediated hepatic lipid accumulation in NAFLD through regulation of miR-206/ARNT axis. Thus, MALAT1/miR-206/ARNT might serve as a therapeutic target against NAFLD.
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Affiliation(s)
- Juan Xiang
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Yuan-Yuan Deng
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Hui-Xia Liu
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Ying Pu
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Ying Pu,
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12
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Lee JH, Moon E, Park J, Oh CE, Hong YR, Yoon M. Optimization of Analysis of Circadian Rest-Activity Rhythm Using Cosinor Analysis in Mice. Psychiatry Investig 2022; 19:380-385. [PMID: 35620823 PMCID: PMC9136527 DOI: 10.30773/pi.2021.0395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/05/2022] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE Data processing in analysis of circadian rhythm was performed in various ways. However, there was a lack of evidence for the optimal analysis of circadian rest-activity rhythm. Therefore, we aimed to perform mathematical simulations of data processing to investigate proper evidence for the optimal analysis of circadian rest-activity rhythm. METHODS Locomotor activities of 20 ICR male mice were measured by infrared motion detectors. The data of locomotor activities was processed using data summation, data average, and data moving average methods for cosinor analysis. Circadian indices were estimated according to time block, respectively. Also, statistical F and p-values were calculated by zero-amplitude test. RESULTS The data moving average result showed well-fitted cosine curves independent of data processing time. Meanwhile, the amplitude, MESOR, and acrophase were properly estimated within 800 seconds in data summation and data average methods. CONCLUSION These findings suggest that data moving average would be an optimal method for data processing in a cosinor analysis and data average within 800-second data processing time might be adaptable. The results of this study can be helpful to analyze circadian restactivity rhythms and integrate the results of the studies using different data processing methods.
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Affiliation(s)
- Jung Hyun Lee
- Department of Pediatrics, Kosin University College of Medicine, Busan, Republic of Korea
| | - Eunsoo Moon
- Department of Psychiatry and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.,Department of Psychiatry, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Jeonghyun Park
- Department of Psychiatry and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Chi Eun Oh
- Department of Pediatrics, Kosin University College of Medicine, Busan, Republic of Korea
| | - Yoo Rha Hong
- Department of Pediatrics, Kosin University College of Medicine, Busan, Republic of Korea
| | - Min Yoon
- Department of Applied Mathematics, Pukyung National University, Busan, Republic of Korea
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13
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Crislip GR, Johnston JG, Douma LG, Costello HM, Juffre A, Boyd K, Li W, Maugans CC, Gutierrez-Monreal M, Esser KA, Bryant AJ, Liu AC, Gumz ML. Circadian Rhythm Effects on the Molecular Regulation of Physiological Systems. Compr Physiol 2021; 12:2769-2798. [PMID: 34964116 PMCID: PMC11514412 DOI: 10.1002/cphy.c210011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Nearly every system within the body contains an intrinsic cellular circadian clock. The circadian clock contributes to the regulation of a variety of homeostatic processes in mammals through the regulation of gene expression. Circadian disruption of physiological systems is associated with pathophysiological disorders. Here, we review the current understanding of the molecular mechanisms contributing to the known circadian rhythms in physiological function. This article focuses on what is known in humans, along with discoveries made with cell and rodent models. In particular, the impact of circadian clock components in metabolic, cardiovascular, endocrine, musculoskeletal, immune, and central nervous systems are discussed. © 2021 American Physiological Society. Compr Physiol 11:1-30, 2021.
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Affiliation(s)
- G. Ryan Crislip
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | - Jermaine G. Johnston
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Hannah M. Costello
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Kyla Boyd
- Department of Biochemistry and Molecular Biology
| | - Wendy Li
- Department of Biochemistry and Molecular Biology
| | | | | | - Karyn A. Esser
- Department of Physiology and Functional Genomics
- Myology Institute
| | | | - Andrew C. Liu
- Department of Physiology and Functional Genomics
- Myology Institute
| | - Michelle L. Gumz
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
- Department of Biochemistry and Molecular Biology
- Department of Physiology and Functional Genomics
- Center for Integrative Cardiovascular and Metabolic Disease
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14
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Munetsuna E, Yamada H, Yamazaki M, Ando Y, Mizuno G, Hattori Y, Kageyama I, Teshigawara A, Nouchi Y, Ishikawa H, Fujii R, Ohta Y, Suzuki K, Shimono Y, Ohashi K, Hashimoto S. Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming. FASEB J 2021; 35:e22030. [PMID: 34748238 DOI: 10.1096/fj.202101276r] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/04/2021] [Accepted: 10/19/2021] [Indexed: 01/08/2023]
Abstract
Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.
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Affiliation(s)
- Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Japan
| | - Mirai Yamazaki
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Japan
| | - Yoshitaka Ando
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Genki Mizuno
- Deparment of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, Toyoake, Japan.,Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Yuji Hattori
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Itsuki Kageyama
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Atsushi Teshigawara
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan.,Deparment of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, Toyoake, Japan
| | - Yuki Nouchi
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Hiroaki Ishikawa
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Koji Ohashi
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Shuji Hashimoto
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Japan
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15
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Ishay Y, Kolben Y, Kessler A, Ilan Y. Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2021; 321:G400-G412. [PMID: 34346773 DOI: 10.1152/ajpgi.00186.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yotam Kolben
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Asa Kessler
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
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16
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Fu Q, North PE, Ke X, Huang YW, Fritz KA, Majnik AV, Lane RH. Adverse Maternal Environment and Postweaning Western Diet Alter Hepatic CD36 Expression and Methylation Concurrently with Nonalcoholic Fatty Liver Disease in Mouse Offspring. J Nutr 2021; 151:3102-3112. [PMID: 34486661 PMCID: PMC8485909 DOI: 10.1093/jn/nxab249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/21/2021] [Accepted: 07/01/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND The role of an adverse maternal environment (AME) in conjunction with a postweaning Western diet (WD) in the development of nonalcoholic fatty liver disease (NAFLD) in adult offspring has not been explored. Likewise, the molecular mechanisms associated with AME-induced NAFLD have not been studied. The fatty acid translocase or cluster of differentiation 36 (CD36) has been implicated to play a causal role in the pathogenesis of WD-induced steatosis. However, it is unknown if CD36 plays a role in AME-induced NAFLD. OBJECTIVE This study was designed to evaluate the isolated and additive impact of AME and postweaning WD on the expression and DNA methylation of hepatic Cd36 in association with the development of NAFLD in a novel mouse model. METHODS AME constituted maternal WD and maternal stress, whereas the control (Con) group had neither. Female C57BL/6J mice were fed a WD [40% fat energy, 29.1% sucrose energy, and 0.15% cholesterol (wt/wt)] 5 wk prior to pregnancy and throughout lactation. Non invasive variable stressors (random frequent cage changing, limited bedding, novel object, etc.) were applied to WD dams during the last third of pregnancy to produce an AME. Con dams consumed the control diet (CD) (10% fat energy, no sucrose or cholesterol) and were not exposed to stress. Male offspring were weaned onto either CD or WD, creating 4 experimental groups: Con-CD, Con-WD, AME-CD, and AME-WD, and evaluated for metabolic and molecular parameters at 120 d of age. RESULTS AME and postweaning WD independently and additively increased the development of hepatic steatosis in adult male offspring. AME and WD independently and additively upregulated hepatic CD36 protein and mRNA expression and hypomethylated promoters 2 and 3 of the Cd36 gene. CONCLUSIONS Using a mouse AME model together with postweaning WD, this study demonstrates a role for CD36 in AME-induced NAFLD in offspring and reveals 2 regions of environmentally induced epigenetic heterogeneity within Cd36.
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Affiliation(s)
- Qi Fu
- Department of Research Administration, Children's Mercy Hospital, Kansas City, MO, USA
| | - Paula E North
- Department of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xingrao Ke
- Department of Research Administration, Children's Mercy Hospital, Kansas City, MO, USA
| | - Yi-Wen Huang
- Department of Obstetrics & Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Katie A Fritz
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
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17
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Pinson MR, Chung DD, Adams AM, Scopice C, Payne EA, Sivakumar M, Miranda RC. Extracellular Vesicles in Premature Aging and Diseases in Adulthood Due to Developmental Exposures. Aging Dis 2021; 12:1516-1535. [PMID: 34527425 PMCID: PMC8407878 DOI: 10.14336/ad.2021.0322] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
The developmental origins of health and disease (DOHaD) is a paradigm that links prenatal and early life exposures that occur during crucial periods of development to health outcome and risk of disease later in life. Maternal exposures to stress, some psychoactive drugs and alcohol, and environmental chemicals, among others, may result in functional changes in developing fetal tissues, creating a predisposition for disease in the individual as they age. Extracellular vesicles (EVs) may be mediators of both the immediate effects of exposure during development and early childhood as well as the long-term consequences of exposure that lead to increased risk and disease severity later in life. Given the prevalence of diseases with developmental origins, such as cardiovascular disease, neurodegenerative disorders, osteoporosis, metabolic dysfunction, and cancer, it is important to identify persistent mediators of disease risk. In this review, we take this approach, viewing diseases typically associated with aging in light of early life exposures and discuss the potential role of EVs as mediators of lasting consequences.
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Affiliation(s)
- Marisa R Pinson
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Dae D Chung
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Amy M Adams
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Chiara Scopice
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Elizabeth A Payne
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Monisha Sivakumar
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Rajesh C Miranda
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, USA
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18
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Peng H, Xu H, Wu J, Li J, Zhou Y, Ding Z, Siwko SK, Yuan X, Schalinske KL, Alpini G, Zhang KK, Xie L. Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease. Liver Int 2021; 41:1305-1319. [PMID: 33529448 PMCID: PMC8137550 DOI: 10.1111/liv.14811] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. METHODS Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. RESULTS The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. CONCLUSIONS Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.
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Affiliation(s)
- Hui Peng
- Department of Nutrition, Texas A&M University, College Station, TX,Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huiting Xu
- Department of Pathology, University of North Dakota, Grand Forks, North Dakota,Hubei Cancer Hospital, Wuhan, Hubei, China
| | - Jie Wu
- Institute of Biosciences & Technology, Texas A&M University, Houston, TX
| | - Jiangyuan Li
- Department of Nutrition, Texas A&M University, College Station, TX,Department of Statistics, Texas A&M University, College Station, TX
| | - Yi Zhou
- Department of Nutrition, Texas A&M University, College Station, TX,Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zehuan Ding
- Department of Nutrition, Texas A&M University, College Station, TX
| | - Stefan K. Siwko
- Institute of Biosciences & Technology, Texas A&M University, Houston, TX
| | - Xianglin Yuan
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kevin L. Schalinske
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA
| | - Gianfranco Alpini
- Richard L. Roudebush VA Medical Center, and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ke K. Zhang
- Department of Nutrition, Texas A&M University, College Station, TX,Institute of Biosciences & Technology, Texas A&M University, Houston, TX,Department of Pathology, University of North Dakota, Grand Forks, North Dakota,Co-corresponding author: These authors contributed equally to this work
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX,Co-corresponding author: These authors contributed equally to this work
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19
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Zeb F, Wu X, Fatima S, Zaman MH, Khan SA, Safdar M, Alam I, Feng Q. Time-restricted feeding regulates molecular mechanisms with involvement of circadian rhythm to prevent metabolic diseases. Nutrition 2021; 89:111244. [PMID: 33930788 DOI: 10.1016/j.nut.2021.111244] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/03/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
Lifestyle and genetic perturbation of circadian rhythm can trigger the incidence and severity of metabolic diseases. Time-restricted feeding (TRF) regulates the circadian rhythm of food intake that protects against metabolic disorders induced by adverse nutrient intake. TRF also executes host metabolism from nutrient availability to optimize nutrient utilization. Circadian clock and nutrient-sensing pathways coordinate to regulate metabolic health through the feeding/fasting cycle. Concurrently, TRF imposes diurnal rhythm in nutrient utilization, thereby preserving cellular homeostasis. However, modulation of daily feeding and fasting periods calibrates the circadian clock, which protects against the lethal effects of nutrient imbalance on metabolism. Therefore, TRF also improves and restores metabolic rhythms that ultimately lead to better fitness by reversing the alteration in genotype-specific gene expression. The aim of this review was to summarize that TRF is an emerging dietary approach that maintains robust circadian rhythms in support of a steady daily feeding and fasting cycle. TRF also encourages the coordination between circadian clock components and nutrient-sensing pathways via molecular effectors that exert a protective role in the prevention of metabolic diseases.
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Affiliation(s)
- Falak Zeb
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Human Nutrition and Dietetics, National University of Medical Sciences, Islamabad, Pakistan.
| | - Xiaoyue Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Sanyia Fatima
- Department of Psychology, Help and Hand Rehabilitation Institute, Ripah International University Islamabad, Pakistan
| | | | - Shahbaz Ali Khan
- Department of Neurosurgery, Ayub Medical College Abbottabad, Pakistan
| | - Mahpara Safdar
- Department of Environmental Design, Health & Nutritional Sciences, Faculty of Sciences, Allama Iqbal Open University, Islamabad, Pakistan
| | - Iftikhar Alam
- Department of Human Nutrition and Dietetics, Bacha Khan University Charsadda KP, Pakistan
| | - Qing Feng
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China
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20
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Ribas-Aulinas F, Ribo S, Parra-Vargas M, Fernández-Pérez A, Cebrià J, Guardiola-Perello M, Ramon-Krauel M, Lerin C, Diaz R, Kalko SG, Vallejo M, Díez-Noguera A, Cambras T, Jimenez-Chillaron JC. Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD. Mol Metab 2021; 45:101162. [PMID: 33422644 PMCID: PMC7851182 DOI: 10.1016/j.molmet.2021.101162] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/28/2020] [Accepted: 01/06/2021] [Indexed: 01/20/2023] Open
Abstract
Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease. OBJECTIVE To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance. METHODS We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model. RESULTS The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1-3 and cryptochrome 1-2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4-6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara). CONCLUSIONS The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm.
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Affiliation(s)
- Francesc Ribas-Aulinas
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Silvia Ribo
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Marcela Parra-Vargas
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Antonio Fernández-Pérez
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain
| | - Judith Cebrià
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Maria Guardiola-Perello
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Marta Ramon-Krauel
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain; Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, Spain
| | - Carles Lerin
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain
| | - Ruben Diaz
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain; Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, Spain
| | | | - Mario Vallejo
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain
| | - Antoni Díez-Noguera
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Spain
| | - Trinitat Cambras
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Spain
| | - Josep C Jimenez-Chillaron
- Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain.
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21
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Thompson MD. Developmental Programming of NAFLD by Parental Obesity. Hepatol Commun 2020; 4:1392-1403. [PMID: 33024911 PMCID: PMC7527686 DOI: 10.1002/hep4.1578] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/08/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
The surge of obesity across generations has become an increasingly relevant issue, with consequences for associated comorbidities in offspring. Data from longitudinal birth cohort studies support an association between maternal obesity and offspring nonalcoholic fatty liver disease (NAFLD), suggesting that perinatal obesity or obesogenic diet exposure reprograms offspring liver and increases NAFLD susceptibility. In preclinical models, offspring exposed to maternal obesogenic diet have increased hepatic steatosis after diet-induced obesity; however, the implications for later NAFLD development and progression are still unclear. Although some models show increased NAFLD incidence and progression in offspring, development of nonalcoholic steatohepatitis with fibrosis may be model dependent. Multigenerational programming of NAFLD phenotypes occurs after maternal obesogenic diet exposure; however, the mechanisms for such programming remain poorly understood. Likewise, emerging data on the role of paternal obesity in offspring NAFLD development reveal incomplete mechanisms. This review will explore the impact of parental obesity and obesogenic diet exposure on offspring NAFLD and areas for further investigation, including the impact of parental diet on disease progression, and consider potential interventions in preclinical models.
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Affiliation(s)
- Michael D. Thompson
- Division of Endocrinology and DiabetesDepartment of PediatricsWashington University School of MedicineSt. LouisMO
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22
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Obesity during pregnancy results in maternal intestinal inflammation, placental hypoxia, and alters fetal glucose metabolism at mid-gestation. Sci Rep 2019; 9:17621. [PMID: 31772245 PMCID: PMC6879619 DOI: 10.1038/s41598-019-54098-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 11/07/2019] [Indexed: 12/18/2022] Open
Abstract
We investigated whether diet-induced changes in the maternal intestinal microbiota were associated with changes in bacterial metabolites and their receptors, intestinal inflammation, and placental inflammation at mid-gestation (E14.5) in female mice fed a control (17% kcal fat, n = 7) or a high-fat diet (HFD 60% kcal fat, n = 9; ad libitum) before and during pregnancy. Maternal diet-induced obesity (mDIO) resulted in a reduction in maternal fecal short-chain fatty acid producing Lachnospiraceae, lower cecal butyrate, intestinal antimicrobial peptide levels, and intestinal SCFA receptor Ffar3, Ffar2 and Hcar2 transcript levels. mDIO increased maternal intestinal pro-inflammatory NFκB activity, colonic CD3+ T cell number, and placental inflammation. Maternal obesity was associated with placental hypoxia, increased angiogenesis, and increased transcript levels of glucose and amino acid transporters. Maternal and fetal markers of gluconeogenic capacity were decreased in pregnancies complicated by obesity. We show that mDIO impairs bacterial metabolite signaling pathways in the mother at mid-gestation, which was associated with significant structural changes in placental blood vessels, likely as a result of placental hypoxia. It is likely that maternal intestinal changes contribute to adverse maternal and placental adaptations that, via alterations in fetal hepatic glucose handling, may impart increased risk of metabolic dysfunction in offspring.
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23
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Szanto KB, Li J, Cordero P, Oben JA. Ethnic differences and heterogeneity in genetic and metabolic makeup contributing to nonalcoholic fatty liver disease. Diabetes Metab Syndr Obes 2019; 12:357-367. [PMID: 30936733 PMCID: PMC6430068 DOI: 10.2147/dmso.s182331] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Obesity is the most prevalent noncommunicable disease in the 21st century, associated with triglyceride deposition in hepatocytes leading to nonalcoholic fatty liver disease (NAFLD). NAFLD is now present in around a third of the world's population. Epidemiological studies have concluded that ethnicity plays a role in complications and treatment response. However, definitive correlations of ethnicity with NAFLD are thoroughly under-reported. A comprehensive review was conducted on ethnic variation in NAFLD patients and its potential role as a crucial effector in complications and treatment response. The highest NAFLD prevalence is observed in Hispanic populations, exhibiting a worse disease progression. In contrast, African-Caribbeans exhibit the lowest risk, with less severe steatosis and inflammation, lower levels of triglycerides, and less metabolic derangement, but conversely higher prevalence of insulin resistance. The prevalence of NAFLD in Asian cohorts is under-reported, although reaching epidemic proportions in these populations. The most well-documented NAFLD patient population is that of Caucasian ethnicity, especially from the US. The relative paucity of available literature suggests there is a vital need for more large-scale multi-ethnic clinical cohort studies to determine the incidence of NAFLD within ethnic groups. This would improve therapy and drug development, as well as help identify candidate gene mutations which may differ within the population based on ethnic background.
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Affiliation(s)
- Krisztina B Szanto
- Faculty of Life Sciences and Medicine, School of Medicine, King's College London, London, UK,
- Institute for Liver and Digestive Health, University College London, London, UK,
| | - Jiawei Li
- Institute for Liver and Digestive Health, University College London, London, UK,
- Institute of Child Health, University College London, London, UK
| | - Paul Cordero
- Institute for Liver and Digestive Health, University College London, London, UK,
| | - Jude A Oben
- Institute for Liver and Digestive Health, University College London, London, UK,
- Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital, NHS Foundation Trust, London, UK
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24
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Menting MD, van de Beek C, Mintjens S, Wever KE, Korosi A, Ozanne SE, Limpens J, Roseboom TJ, Hooijmans C, Painter RC. The link between maternal obesity and offspring neurobehavior: A systematic review of animal experiments. Neurosci Biobehav Rev 2019; 98:107-121. [DOI: 10.1016/j.neubiorev.2018.12.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 12/19/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023]
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25
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Zhou L, Kang L, Xiao X, Jia L, Zhang Q, Deng M. "Gut Microbiota-Circadian Clock Axis" in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism. Int J Endocrinol 2019; 2019:5893028. [PMID: 31534453 PMCID: PMC6732598 DOI: 10.1155/2019/5893028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023] Open
Abstract
The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the "metabolic memory" and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of "metabolic memory" has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the "gut microbiota-circadian clock axis" might be a novel and crucial mechanism to decipher "metabolic memory." The "gut microbiota-circadian clock axis" is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.
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Affiliation(s)
- Liyuan Zhou
- Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lin Kang
- Department of Endocrinology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lijing Jia
- Department of Endocrinology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Mingqun Deng
- Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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26
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Puppala S, Li C, Glenn JP, Saxena R, Gawrieh S, Quinn A, Palarczyk J, Dick EJ, Nathanielsz PW, Cox LA. Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation. J Physiol 2018; 596:5823-5837. [PMID: 29516496 PMCID: PMC6265567 DOI: 10.1113/jp275422] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/01/2018] [Indexed: 12/12/2022] Open
Abstract
KEY POINTS Maternal obesity (MO) and exposure to a high-fat, high-simple-carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. ABSTRACT Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life-course health outcomes. Little is known about the molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high-fat, high-fructose diet. Unbiased gene and microRNA (small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by the Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/β-catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the non-human primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential microRNA epigenetic regulators of metabolic disruption.
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Affiliation(s)
- Sobha Puppala
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest BaptistMedical CenterWinston‐SalemNCUSA
| | - Cun Li
- Department of Animal ScienceUniversity of WyomingLaramieWYUSA
| | - Jeremy P. Glenn
- Department of GeneticsTexas Biomedical Research InstituteSan AntonioTXUSA
| | - Romil Saxena
- Department of Pathology, Indiana University School of MedicineIndianapolisINUSA
| | - Samer Gawrieh
- Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisINUSA
| | - Amy Quinn
- Department of Pediatrics, Division of NeonatologyUniversity of Texas Health Science CenterSan AntonioTXUSA
| | - Jennifer Palarczyk
- Department of Pediatrics, Division of NeonatologyUniversity of Texas Health Science CenterSan AntonioTXUSA
| | - Edward J. Dick
- Southwest National Primate Research CenterTexas Biomedical Research InstituteSan AntonioTXUSA
| | - Peter W. Nathanielsz
- Department of Animal ScienceUniversity of WyomingLaramieWYUSA
- Department of GeneticsTexas Biomedical Research InstituteSan AntonioTXUSA
| | - Laura A. Cox
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest BaptistMedical CenterWinston‐SalemNCUSA
- Southwest National Primate Research CenterTexas Biomedical Research InstituteSan AntonioTXUSA
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27
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Spradley FT, Smith JA, Alexander BT, Anderson CD. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab 2018; 315:E795-E814. [PMID: 29509436 PMCID: PMC6293166 DOI: 10.1152/ajpendo.00394.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and nonalcoholic fatty liver disease (NAFLD). It is unclear whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled type 2 diabetes mellitus, which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those proinflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD.
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Affiliation(s)
- Frank T Spradley
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Jillian A Smith
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Barbara T Alexander
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
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28
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Maternal high-fat diet consumption induces sex-dependent alterations of the endocannabinoid system and redox homeostasis in liver of adult rat offspring. Sci Rep 2018; 8:14751. [PMID: 30282988 PMCID: PMC6170403 DOI: 10.1038/s41598-018-32906-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 09/17/2018] [Indexed: 01/23/2023] Open
Abstract
Maternal diet plays a critical role in health development. Perinatal overnutrition induces metabolic dysfunctions and obesity in the offspring. Obesity is associated with endocannabinoid system (ECS) over activation and oxidative stress. Liver ECS activation induces hepatic steatosis, inflammation and fibrosis while the antagonism of cannabinoid receptors ameliorates these alterations. Here, we investigated the effect of perinatal maternal high-fat diet (HF, 29% of calories as fat) on the ECS and antioxidant system in liver of male and female adult rat offspring (180 days old). Maternal HF diet increased hepatic cannabinoid receptors, ECS metabolizing enzymes and triglyceride content, with male offspring more affected. ECS changes are likely independent of estradiol serum levels but associated with increased hepatic content of estrogen receptor, which can stimulate the expression of ECS components. Differently, maternal HF diet decreased the activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase, and increased oxidative stress markers in both sexes. Alterations in the redox homeostasis were associated with mitochondria damage but not with liver fibrosis. Our data suggest that maternal HF diet induces ECS over activation in adulthood, and that male offspring are at higher risk to develop liver disease compared with female rats.
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29
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Cai J, Zhang XJ, Li H. Progress and challenges in the prevention and control of nonalcoholic fatty liver disease. Med Res Rev 2018; 39:328-348. [PMID: 29846945 DOI: 10.1002/med.21515] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 05/02/2018] [Accepted: 05/12/2018] [Indexed: 12/17/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. Individuals with NAFLD have a high frequency of developing progressive liver disease and metabolism-related comorbidities, which result from of a lack of awareness and poor surveillance of the disease and a paucity of approved and effective therapies. Managing the complications of NAFLD has already begun to place a tremendous burden on health-care systems. Although efforts to identify effective therapies are underway, the lack of validated preclinical NAFLD models that represent the biology and outcomes of human disease remains a major barrier. This review summarizes the characteristics and prevalence of the disease and the status of our understanding of its mechanisms and potential therapeutic targets.
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Affiliation(s)
- Jingjing Cai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.,Institute of Model Animal of Wuhan University, Wuhan, China
| | - Xiao-Jing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Institute of Model Animal of Wuhan University, Wuhan, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Institute of Model Animal of Wuhan University, Wuhan, China.,Basic Medical School, Wuhan University, Wuhan, China
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30
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Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS One 2018; 13:e0192606. [PMID: 29447215 PMCID: PMC5813940 DOI: 10.1371/journal.pone.0192606] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 01/28/2018] [Indexed: 12/18/2022] Open
Abstract
We investigated maternal obesity in inbred SM/J mice by assigning females to a high-fat diet or a low-fat diet at weaning, mating them to low-fat-fed males, cross-fostering the offspring to low-fat-fed SM/J nurses at birth, and weaning the offspring onto a high-fat or low-fat diet. A maternal high-fat diet exacerbated obesity in the high-fat-fed daughters, causing them to weigh more, have more fat, and have higher serum levels of leptin as adults, accompanied by dozens of gene expression changes and thousands of DNA methylation changes in their livers and hearts. Maternal diet particularly affected genes involved in RNA processing, immune response, and mitochondria. Between one-quarter and one-third of differentially expressed genes contained a differentially methylated region associated with maternal diet. An offspring high-fat diet reduced overall variation in DNA methylation, increased body weight and organ weights, increased long bone lengths and weights, decreased insulin sensitivity, and changed the expression of 3,908 genes in the liver. Although the offspring were more affected by their own diet, their maternal diet had epigenetic effects lasting through adulthood, and in the daughters these effects were accompanied by phenotypic changes relevant to obesity and diabetes.
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31
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Crew RC, Waddell BJ, Mark PJ. Obesity-induced changes in hepatic and placental clock gene networks in rat pregnancy†. Biol Reprod 2017; 98:75-88. [DOI: 10.1093/biolre/iox158] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 11/24/2017] [Indexed: 12/13/2022] Open
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32
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Cordero P, Li J, Nguyen V, Pombo J, Maicas N, Novelli M, Taylor PD, Samuelsson AM, Vinciguerra M, Oben JA. Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System. Nutrients 2017; 9:E1041. [PMID: 28930194 PMCID: PMC5622801 DOI: 10.3390/nu9091041] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 12/13/2022] Open
Abstract
Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system.
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Affiliation(s)
- Paul Cordero
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK.
| | - Jiawei Li
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK.
| | - Vi Nguyen
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK.
| | - Joaquim Pombo
- Division of Women's Health, Faculty of Life Sciences & Medicine, King's College London, London SE1 7EH, UK.
| | - Nuria Maicas
- Division of Women's Health, Faculty of Life Sciences & Medicine, King's College London, London SE1 7EH, UK.
| | - Marco Novelli
- Department of Pathology, University College London, London WC1E 6JJ, UK.
| | - Paul D Taylor
- Division of Women's Health, Faculty of Life Sciences & Medicine, King's College London, London SE1 7EH, UK.
| | - Anne-Maj Samuelsson
- Division of Women's Health, Faculty of Life Sciences & Medicine, King's College London, London SE1 7EH, UK.
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK.
- Center for Translational Medicine, International Clinical Research Center (FNUSA-ICRC), Brno 65691, Czech Republic.
| | - Jude A Oben
- Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK.
- Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital, NHS Foundation Trust, London SE1 7EH, UK.
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O'Neil DS, Stewart CJ, Chu DM, Goodspeed DM, Gonzalez-Rodriguez PJ, Shope CD, Aagaard KM. Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding. Am J Obstet Gynecol 2017; 217:218.e1-218.e15. [PMID: 28373017 PMCID: PMC5545073 DOI: 10.1016/j.ajog.2017.03.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 03/03/2017] [Accepted: 03/23/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND We have recently shown in both non-human primates and in rodents that fetal and neonatal hepatic expression of the circadian transcription factor, Npas2, is modulated by a high fat maternal diet and plays a critical role in establishing life-long metabolic homeostasis. Similarly, we and others have also established the importance of the maternal and early postnatal diet on establishment of the early gut microbiome. OBJECTIVE We hypothesized that altered circadian gene expression solely in the neonatal liver would result in gut microbiome dysbiosis, especially with diet-induced metabolic stress (ie, restricted feeding). Using a murine model in which we conditionally knock out Npas2 in the neonatal liver, we aimed to determine the role of the circadian machinery in gut dysbiosis with restricted feeding. STUDY DESIGN We collected fecal samples from liver Npas2 conditional knockout (n = 11) and wild-type (n = 13) reproductive-aged mice before (study day 0) and after the restricted feeding study (study day 17). Extracted DNA was sequenced using the MiSeq Illumina platform using primers specific for the V4 region of the 16S ribosomal DNA gene. The resulting sequences were quality filtered, aligned, and assigned taxonomy. Principal coordinate analysis was performed on unweighted and weighted UniFrac distances between samples with a permutation analysis of variance to assess clustering significance between groups. Microbial taxa that significantly differ between groups of interest was determined using linear discriminate analysis effect size and randomForrest. RESULTS Principal coordinate analysis performed on weighted UniFrac distances between male conditional knockout and wild-type cohorts revealed that the gut microbiome of the mice did not differ by genotype at the start of the restricted feeding study but did differ by virtue of genotype at the end of the study (P = .001). Moreover, these differences could be at least partially attributed to restricted feeding-associated alterations in relative abundance of the Bacteroides genus, which has been implicated as crucial to establishing a healthy gut microbiome early in development. CONCLUSION Here we have provided an initial key insight into the interplay between neonatal establishment of the peripheral circadian clock in the liver and the ability of the gut microbiome to respond to dietary and metabolic stress. Because Npas2 expression in the liver is a target of maternal high-fat diet-induced metabolic perturbations during fetal development, we speculate that these findings have potential implications in the long-term metabolic health of their offspring.
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Affiliation(s)
- Derek S O'Neil
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX; Interdepartmental Graduate Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX
| | - Christopher J Stewart
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX
| | - Derrick M Chu
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX; Interdepartmental Graduate Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX
| | - Danielle M Goodspeed
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX
| | - Pablo J Gonzalez-Rodriguez
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX
| | - Cynthia D Shope
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX
| | - Kjersti M Aagaard
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX; Department of Molecular and Cellular Physiology, Baylor College of Medicine, Houston, TX; Interdepartmental Graduate Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX.
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Wankhade UD, Zhong Y, Kang P, Alfaro M, Chintapalli SV, Thakali KM, Shankar K. Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations. PLoS One 2017; 12:e0175675. [PMID: 28414763 PMCID: PMC5393586 DOI: 10.1371/journal.pone.0175675] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 03/29/2017] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated. METHODS Two independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups. RESULTS When compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7-8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum. CONCLUSION Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.
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Affiliation(s)
- Umesh D. Wankhade
- Arkansas Children’s Nutrition Center, Little Rock, Arkansas, United States of America
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Ying Zhong
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Ping Kang
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Maria Alfaro
- Molecular Genetic Pathology Laboratory, Arkansas Children’s Hospital, Little Rock, Arkansas, United States of America
| | - Sree V. Chintapalli
- Arkansas Children’s Nutrition Center, Little Rock, Arkansas, United States of America
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Keshari M. Thakali
- Arkansas Children’s Nutrition Center, Little Rock, Arkansas, United States of America
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Kartik Shankar
- Arkansas Children’s Nutrition Center, Little Rock, Arkansas, United States of America
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
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Bluemel S, Williams B, Knight R, Schnabl B. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am J Physiol Gastrointest Liver Physiol 2016; 311:G1018-G1036. [PMID: 27686615 PMCID: PMC5206291 DOI: 10.1152/ajpgi.00245.2016] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/25/2016] [Indexed: 02/08/2023]
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) represent a major health burden in industrialized countries. Although alcohol abuse and nutrition play a central role in disease pathogenesis, preclinical models support a contribution of the gut microbiota to ALD and NAFLD. This review describes changes in the intestinal microbiota compositions related to ALD and NAFLD. Findings from in vitro, animal, and human studies are used to explain how intestinal pathology contributes to disease progression. This review summarizes the effects of untargeted microbiome modifications using antibiotics and probiotics on liver disease in animals and humans. While both affect humoral inflammation, regression of advanced liver disease or mortality has not been demonstrated. This review further describes products secreted by Lactobacillus- and microbiota-derived metabolites, such as fatty acids and antioxidants, that could be used for precision medicine in the treatment of liver disease. A better understanding of host-microbial interactions is allowing discovery of novel therapeutic targets in the gut microbiota, enabling new treatment options that restore the intestinal ecosystem precisely and influence liver disease. The modulation options of the gut microbiota and precision medicine employing the gut microbiota presented in this review have excellent prospects to improve treatment of liver disease.
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Affiliation(s)
- Sena Bluemel
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Brandon Williams
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Rob Knight
- Departments of Pediatrics and Computer Science and Engineering, University of California San Diego, La Jolla, California; and
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California;
- Veterans Affairs San Diego Healthcare System, San Diego, California
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Soeda J, Cordero P, Li J, Mouralidarane A, Asilmaz E, Ray S, Nguyen V, Carter R, Novelli M, Vinciguerra M, Poston L, Taylor PD, Oben JA. Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity. Int J Food Sci Nutr 2016; 68:455-466. [PMID: 27899042 PMCID: PMC5399811 DOI: 10.1080/09637486.2016.1261086] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.
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Affiliation(s)
- Junpei Soeda
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Paul Cordero
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Jiawei Li
- a Institute for Liver and Digestive Health, University College London , London , UK
| | | | - Esra Asilmaz
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Shuvra Ray
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Vi Nguyen
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Rebeca Carter
- a Institute for Liver and Digestive Health, University College London , London , UK
| | - Marco Novelli
- b Department of Pathology , University College London , London , UK
| | - Manlio Vinciguerra
- a Institute for Liver and Digestive Health, University College London , London , UK.,c Fondazione Italiana Fegato , Area Science Park , Basovizza , Trieste , Italy.,d Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital , Brno , Czech Republic
| | - Lucilla Poston
- e Division of Women's Health , King's College London , London , UK
| | - Paul D Taylor
- e Division of Women's Health , King's College London , London , UK
| | - Jude A Oben
- a Institute for Liver and Digestive Health, University College London , London , UK.,f Department of Gastroenterology and Hepatology , Guy's and St Thomas' Hospital, NHS Foundation Trust , London , UK
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A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence. Int J Mol Sci 2016; 17:ijms17060947. [PMID: 27314342 PMCID: PMC4926480 DOI: 10.3390/ijms17060947] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 06/06/2016] [Accepted: 06/07/2016] [Indexed: 02/07/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%–20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, ”paediatric” NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention.
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Soeda J, Mouralidarane A, Cordero P, Li J, Nguyen V, Carter R, Kapur SR, Pombo J, Poston L, Taylor PD, Vinciguerra M, Oben JA. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. J Physiol Biochem 2016; 72:281-91. [PMID: 26979740 PMCID: PMC4873529 DOI: 10.1007/s13105-016-0476-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/29/2016] [Indexed: 12/11/2022]
Abstract
The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults.
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Affiliation(s)
- Jumpei Soeda
- Institute for Liver and Digestive Health, University College London, London, UK
| | | | - Paul Cordero
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Jiawei Li
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Vi Nguyen
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Rebeca Carter
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Sabrina R Kapur
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Joaquim Pombo
- Division of Women's Health, King's College London, London, UK
| | - Lucilla Poston
- Division of Women's Health, King's College London, London, UK
| | - Paul D Taylor
- Division of Women's Health, King's College London, London, UK
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, University College London, London, UK.
- International Clinical Research Center (ICRC), Center for Translational Medicine (CTM), St. Anne's University Hospital, Brno, Czech Republic.
- Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy.
| | - Jude A Oben
- Institute for Liver and Digestive Health, University College London, London, UK.
- Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital, NHS Foundation Trust, London, UK.
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Bruce KD, Szczepankiewicz D, Sihota KK, Ravindraanandan M, Thomas H, Lillycrop KA, Burdge GC, Hanson MA, Byrne CD, Cagampang FR. Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:584-93. [PMID: 27040510 PMCID: PMC4874946 DOI: 10.1016/j.bbalip.2016.03.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 03/07/2016] [Accepted: 03/25/2016] [Indexed: 02/06/2023]
Abstract
Background We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear. Aims Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life. Methods Female mice were fed either a control (C, 7% kcal fat) or HF (45% kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, sirtuin expression (Sirt1, Sirt3), and the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erbα, Rev-Erbβ, RORα, and Srebp1c) were measured in offspring livers. Results Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD+/NADH (p < 0.05, HF/HF vs C/C), Sirt1 (p < 0.001, HF/HF vs C/C), Sirt3 (p < 0.01, HF/HF vs C/C), perturbed clock gene expression, and elevated expression of genes involved lipid metabolism, such as Srebp1c (p < 0.05, C/HF and HF/HF vs C/C). Conclusion Our results suggest that exposure to excess dietary fat during early and post-natal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced sirtuin abundance, and desynchronized clock gene expression.
Offspring of mothers fed a high fat diet show severe fatty liver in later life. HF feeding is associated with altered cellular redox status and reduced sirtuin gene expression. HF feeding desynchronises the expression of core clock genes and lipogenic transcription factors. Exposure to a HF diet during development causes changes in liver metabolism that precede severe fatty liver disease.
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Affiliation(s)
- Kimberley D Bruce
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK; University of Colorado Anschutz Medical Campus, Endocrinology, Metabolism and Diabetes, Aurora, USA.
| | - Dawid Szczepankiewicz
- Poznań University of Life Sciences, Department of Animal Physiology and Biochemistry, Poznań, Poland
| | - Kiran K Sihota
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Manoj Ravindraanandan
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Hugh Thomas
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Karen A Lillycrop
- Centre for Biological Sciences, Institute of Developmental Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK
| | - Graham C Burdge
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Mark A Hanson
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Christopher D Byrne
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Felino R Cagampang
- Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
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Neary R, Watson CJ, Baugh JA. Epigenetics and the overhealing wound: the role of DNA methylation in fibrosis. FIBROGENESIS & TISSUE REPAIR 2015; 8:18. [PMID: 26435749 PMCID: PMC4591063 DOI: 10.1186/s13069-015-0035-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 09/04/2015] [Indexed: 12/20/2022]
Abstract
Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterised by the excessive deposition of extracellular matrix proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Although a considerable amount of research has focused on the mechanisms underlying disease pathogenesis, current therapeutic options do not directly target the pro-fibrotic process. As a result, there is a clear unmet clinical need to develop new agents. Novel findings implicate a role for epigenetic modifications contributing to the progression of fibrosis by alteration of gene expression profiles. This review will focus on DNA methylation; its association with fibroblast differentiation and activation and the consequent buildup of fibrotic scar tissue. The potential use of therapies that modulate this epigenetic pathway for the treatment of fibrosis in several organ systems is also discussed.
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Affiliation(s)
- Roisin Neary
- UCD School of Medicine and Medical Science, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4 Ireland
| | - Chris J Watson
- UCD School of Medicine and Medical Science, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4 Ireland
| | - John A Baugh
- UCD School of Medicine and Medical Science, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4 Ireland
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