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Prolactin regulatory element-binding (PREB) protein regulates hepatic glucose homeostasis
Park, Joo-Man,Kim, Mi-Young,Kim, Tae-Hyun,Min, Dong-Kook,Yang, Ga Eul,Ahn, Yong-Ho Elsevier 2018 Biochimica et biophysica acta Vol.1864 No.6
<P><B>Abstract</B></P> <P>Prolactin regulatory element-binding (PREB) protein is a transcription factor that regulates prolactin (PRL) gene expression. PRL, also known as luteotropic hormone or luteotropin, is well known for its role in producing milk. However, the role of PREB, in terms of hepatic glucose metabolism, is not well elucidated. Here, we observed expression of <I>Preb</I> in the mouse liver, in connection with glucose homeostasis. Morevoer, <I>Preb</I> was downregulated in <I>db/db</I>, <I>ob/ob</I> and high-fat diet-induced obese (DIO) mice, concurrent with upregulation of the liver genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase-1 (Pck). Administration of adenovirus-<I>Preb</I> (Ad-<I>Preb</I>) to <I>db/db</I>, <I>ob/ob</I>, and DIO mice diminished glucose, insulin, and pyruvate tolerance, which analogously, were impaired in normal (C57BL/6) mice knocked down for <I>Preb</I>, via infection with Ad-<I>shPreb</I> (anti-<I>Preb</I> RNA), indicating Preb to be a negative regulator of liver gluconeogenic genes. We further demonstrate that Preb negatively influences gluconeogenic gene expression, by directly binding to their promoters at a prolactin core-binding element (PCBE).</P> <P>A better understanding of <I>Preb</I> gene expression, during the pathogenesis of hepatic insulin resistance, could ultimately provide new avenues for therapies for metabolic syndrome, obesity, and type-2 diabetes mellitus, disorders whose worldwide incidences are increasing drastically.</P> <P><B>Highlights</B></P> <P> <UL> <LI> PREB expression is decreased in fasting states and insulin-resistant diabetic model mice. </LI> <LI> Glucose homeostasis is improved by Ad-<I>Preb</I> administration in diabetic model mice. </LI> <LI> PREB directly binds to PCBE on promoter of gluconeogenic genes. </LI> <LI> The protein levels of PREB is regulated by hormones (cAMP and insulin). </LI> </UL> </P>
Lee Min Hak,Lee Bada,Park Se Eun,Yang Ga Eul,Cheon Seungwoo,Lee Dae Hoon,Kang Sukyeong,Sun Ye Ji,Kim Yongjin,Jung Dong-sub,Kim Wonwoo,Kang Jihoon,Kim Yi Rang,Choi Jin Woo 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-
Sarcopenia, the progressive decline in skeletal muscle mass and function, is observed in various conditions, including cancer and aging. The complex molecular biology of sarcopenia has posed challenges for the development of FDA-approved medications, which have mainly focused on dietary supplementation. Targeting a single gene may not be sufficient to address the broad range of processes involved in muscle loss. This study analyzed the gene expression signatures associated with cancer formation and 5-FU chemotherapy-induced muscle wasting. Our findings suggest that dimenhydrinate, a combination of 8-chlorotheophylline and diphenhydramine, is a potential therapeutic for sarcopenia. In vitro experiments demonstrated that dimenhydrinate promotes muscle progenitor cell proliferation through the phosphorylation of Nrf2 by 8-chlorotheophylline and promotes myotube formation through diphenhydramine-induced autophagy. Furthermore, in various in vivo sarcopenia models, dimenhydrinate induced rapid muscle tissue regeneration. It improved muscle regeneration in animals with Duchenne muscular dystrophy (DMD) and facilitated muscle and fat recovery in animals with chemotherapy-induced sarcopenia. As an FDA-approved drug, dimenhydrinate could be applied for sarcopenia treatment after a relatively short development period, providing hope for individuals suffering from this debilitating condition.