Peroxisome proliferator‐activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Pleniceanu, Oren; Shukrun, Racheli; Omer, Dorit; Vax, Einav; Kanter, Itamar; Dziedzic, Klaudyna; Pode‐Shakked, Naomi; Mark-Daniei, Michal; Pri‐Chen, Sara; Gnatek, Yehudit; Alfandary, Hadas; Varda‐Bloom, Nira; Bar-Lev, Dekel D.; Bollag, Naomi; Shtainfeld, Rachel; Armon, Leah; Urbach, Achia; Kalisky, Tomer; Nagler, Arnon; Harari‐Steinberg, Orit; Arbiser, Jack L.; Dekel, Benjamin

doi:10.15252/emmm.201506111

Cited by 12 publications

(8 citation statements)

References 102 publications

(137 reference statements)

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“…5–6). To elucidate whether PPARγ mediates the regulation of adipogenesis by HSPA12A, we followed the differentiation of normal control (NC) and HSPA12A - overexpressing ( Hspa12a o/e ) 3T3-L1 cells in the presence or absence of a potent specific PPARγ inhibitor (GW9662) [26]. Similar to the observations made in primary SVF (Fig.…”

Section: Resultsmentioning

confidence: 99%

HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ

Zhang

Chen

et al. 2019

Cell Death Differ

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Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a−/−) in mice attenuated high-fat diet (HFD)-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia compared to their wild type (WT) littermates. Increased insulin sensitivity was observed in Hspa12a−/− mice compared to WT mice. The HFD-induced upregulation of PPARγ and its target adipogenic genes in white adipose tissues (WAT) of Hspa12a−/− mice were also attenuated. Loss- and gain-of-function studies revealed that the differentiation of primary adipocyte precursors, as well as the expression of PPARγ and target adipogenic genes during the differentiation, was suppressed by HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A expression was downregulated by PPARγ inhibition but upregulated by PPARγ activation in primary adipocytes. A direct binding of PPARγ to the PPAR response element in the Hspa12a promoter region was confirmed by chromatin immunoprecipitation assay, and this binding was increased after differentiation of primary adipocytes. These findings indicate that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans.

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Section: Resultsmentioning

confidence: 99%

HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ

Zhang

Chen

et al. 2019

Cell Death Differ

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“…Atherosclerosis as a chronic and progressive disease usually starts with damage of the endothelial layer of an artery. Hypertension, hyperglycemia, hyperlipidemia especially hypercholesterolemia, smoking, obesity and diabetes, certain inflammatory disorders such as arthritis, infections, and drugs are the common risk factors of atherosclerotic plaque formation (7,8). Of interest, high incidences of myocardial infarction and stroke have been associated with colder ambient temperature and cold seasons (9,10).…”

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confidence: 99%

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

Sui

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E −/− (ApoE −/− ) and low-density lipoprotein (LDL) receptor −/− (Ldlr −/− ) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis. mirabegron | atherosclerosis | plaque instability | lipolysis | adipose tissue A therosclerosis, the thickening, hardening, and loss of elasticity of the arterial vessel wall, is the major cause of morbidity and mortality worldwide (1-4). Atherosclerotic lesions containing fatty plaques, cholesterol, and inflammatory cells are the primary causes of cardiovascular disease and stroke (5, 6). Atherosclerosis as a chronic and progressive disease usually starts with damage of the endothelial layer of an artery. Hypertension, hyperglycemia, hyperlipidemia especially hypercholesterolemia, smoking, obesity and diabetes, certain inflammatory disorders such as arthritis, infections, and drugs are the common risk factors of atherosclerotic plaque formation (7,8). Of interest, high incidences of myocardial infarction and stroke have been associated with colder ambient temperature and cold seasons (9, 10). Although the exact mechanism underlying low ambient temperature has not been elucidated, our recent findings show that cold-induced lipolysis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT) may partly explain the high incidences of cardiovascular disease and stroke (11).The balance between energy deposition and dissipation is regulated by multiple factors, including the central nervous system, the endocrine system, food intake, physical exercise, pathological disease, and medications (12,13). Although WAT stores excessive energy in its lipid form, activated BAT specializes energy consumption by producing heat (14,15). Under certain conditions such as cold exposure, WAT, especially that located in the s.c. region, undergoes the brown-like transition, a process named browning WAT (16,17). Instead of stor...

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“…29 Moreover, targeting LXRb and PPARg has been reported as a promising therapeutic approach to modulate tumor progression. 30,31 Taken together, our results show that the development of quercetin-APL conjugates may provide a new strategy for generating drug candidates against cancer and other diseases related to abnormal lipid accumulation.…”

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confidence: 60%

Flavonoid–alkylphospholipid conjugates elicit dual inhibition of cancer cell growth and lipid accumulation

et al. 2019

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Peroxisome proliferator‐activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Cited by 12 publications

References 102 publications

HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ

HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

Flavonoid–alkylphospholipid conjugates elicit dual inhibition of cancer cell growth and lipid accumulation

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