Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes

Wu, Chunyan; Jia, Yongyi; Lee, Ji Hae; Kim, Yeonji; Sekharan, Sivakumar; Batista, Víctor S.; Lee, Sung Joon

doi:10.1016/j.biocel.2015.03.008

Cited by 50 publications

(52 citation statements)

References 35 publications

(41 reference statements)

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“…Glucocorticoids directly upregulate lipin-1 expression (Manmontri et al 2008), representing an intriguing mechanism driving hepatic steatosis by simultaneously decreasing lipid oxidation and increasing DNL and triglyceride esterification. By removing hairy enhancer of split 1 (Hes1), a negative regulator of PPARg expression, hepatic glucocorticoid signaling enhances PPARg expression (Revollo et al 2013, Wu et al 2015. In obese db/db mice, transgenic overexpression of Hes1 prevents PPARg upregulation and corrects fatty liver (Lemke et al 2008).…”

Section: De Novo Lipogenesismentioning

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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Section: De Novo Lipogenesismentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

153

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“…Recent studies have highlighted the finding that ORs have diverse functions in various tissues in connection to several physiological contexts beyond odor recognition: MOR17-4 controls cellular motility and chemotaxis in sperm cells (5); OR1A1 modulates hepatic triglyceride metabolism in human hepatocytes through the PKA signaling pathway (6); Olfr78 functions as a renal short-chain fatty acid receptor involved in the regulation of renin secretion and blood pressure in the renal juxtaglomerular apparatus (7) and as a hypoxia sensor in the breathing circuit and stimulator of carotid sinus nerve activity in response to lactate in glomus cells (8); and MOR23 mediates signal transduction in myocytes for muscle regeneration and repair in skeletal muscle (9). These reports suggest that the diverse functions of ORs might include the regulation of energy metabolism; however, the roles of ORs in metabolic tissues are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats

Wu¹,

Hwang²,

Jia³

et al. 2017

Journal of Clinical Investigation

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“…Recently, ORs came into the focus of drug development because ectopically expressed ORs were involved in physiological and pathophysiological mechanisms within human tissues, such as the chemotaxis of sperm, the proliferation of prostate cancer and liver cancer cells, the induction of wound-healing, the modulation of hepatic triglyceride metabolism, cytokinesis, apoptosis and the regulation of serotonin secretion [8, 13, 58, 60, 67, 79, 82, 90, 99, 108, 114]. …”

Section: Introductionmentioning

confidence: 99%

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

et al. 2017

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Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+ imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0600-y) contains supplementary material, which is available to authorized users.

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Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes

Cited by 50 publications

References 35 publications

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

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