Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Souza-Mello, Vanessa

doi:10.4254/wjh.v7.i8.1012

Cited by 150 publications

(110 citation statements)

References 84 publications

(86 reference statements)

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“…7). By having opposite functions, Pparα and Pparγ regulate fat metabolism and while Pparγ promotes lipid storage and Pparα promotes lipid utilization (Ables 2012, Kawano & Cohen 2013, Souza-Mello 2015. In the present study, prenatal hyperandrogenization decreased Pparα levels in the liver of PHanov animals, suggesting that this group could be more sensitive to hepatic steatosis.…”

Section: Discussionsupporting

confidence: 48%

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

Abruzzese

Heber

Ferreira

et al. 2016

Journal of Endocrinology

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Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. Androgen excess alters liver lipid metabolism

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Section: Discussionsupporting

confidence: 48%

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

Abruzzese

Heber

Ferreira

et al. 2016

Journal of Endocrinology

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“…Taken together, these findings suggest that the identified miRNA-targeted genes contribute to regulating genes and pathways that are involved in adipogenesis, which may help to define the fat deposition differences between two groups of pigs. Recently, it has been shown that targeting PPARs is a potential way to treat NAFLDs [63,64]. Since the miRNAs that we uncovered in our study regulate the PPAR pathway, this study helps us understand the players involved in the regulation of this pathway and could provide insights into better treatment for NAFLDs.…”

Section: Discussionmentioning

confidence: 92%

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

Zhang¹,

Huang²,

Guo³

et al. 2017

Oncotarget

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The domestic pig, an important species in the animal production industry, is also a model system for studying fat deposition and fat-associated diseases in humans. In order to investigate the genetic relationships of the miRNAs that may regulate fat deposition, we performed a genome-wide analysis of miRNAs derived from subcutaneous adipose tissue of Laiwu and Large White pig using RNA-seq. A total of 26,486,906 reads were obtained. Further analysis indicated that 39 known miRNAs and 56 novel miRNAs had significantly differential expression between the two breeds of pigs. Gene Ontology and KEGG pathway analysis revealed that the predicted targets of these differentially expressed miRNAs were involved in several fat-associated pathways, such as the PPAR, MAPK and Wnt signaling pathways. In addition, we found that three miRNAs, ssc-miR-133a-3p, ssc-miR-486 and ssc-miR-1, had an impact on the development of porcine subcutaneous fat through the PPAR signaling pathway. This study provides clues to understand the potential mechanisms of adipogenesis and fat deposition between two different pig breeds. Furthermore, these results may also contribute to the research involving human obesity.

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“…In both alcohol-and methionine-choline-deficient models of hepatic lipid accumulation, elimination of PPARa signaling increases the resulting hepatic lipid accumulation (Ip et al 2003. Accordingly, PPARa agonist treatment in fatty liver models consistently decreases hepatic steatosis (Ide et al 2004, Larter et al 2012, Barbosa-da-Silva et al 2015, Souza-Mello 2015.…”

Section: Hepatic Lipids As Signaling Moleculesmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

153

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Cited by 150 publications

References 84 publications

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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