Abstract
Pathologically elevated hepatic glucose production is one of the most important etiologies of type 2 diabetes mellitus (T2DM). The underlying molecular mechanism remains ill-defined. Uridine is the most abundant nucleoside in circulation. Blood uridine level is stably maintained in mammals since excess uridine promotes spontaneous tumorigenesis. We recently showed that adipose tissue is a novel site to supply uridine in addition to the liver (Deng Y, et al., Science, 2017). Obesity, a condition with increased fat mass, is therefore associated with a higher supply of uridine from adipose tissue. To maintain homeostatic circulating uridine level in obesity, de novo uridine synthesis in hepatocytes will need to be reduced. Consistent with this notion, we found that Cad, the rate-limiting enzyme for uridine synthesis, is decreased in the liver by HFD feeding. Aspartate (Asp) is a key substrate for hepatic uridine synthesis. Importantly, Asp is also an essential substrate for hepatic glucose production. Therefore, the reduction of uridine biosynthesis in obesity (more Asp is available) may increase hepatic glucose production. Conversely, upregulation of uridine synthesis may suppress glucose output and type 2 diabetes. Based on this rationale, we hypothesize that hepatic uridine synthesis and glucose production are reciprocally regulated and reduced liver uridine synthesis is a main cause for elevated hepatic glucose production in obesity and T2DM. To test this hypothesis, we engineered a mouse model in which Cad is deleted in hepatocytes. Preliminary data showed that liver gluconeogenetic pathway was upregulated by Cad deletion. Consistently, PALA, an inhibitor of uridine synthesis, caused an acute elevation in blood glucose (hyperglycemia), again supporting a role of uridine synthesis in hepatic glycemic control. We further showed that XBP1s, the most conserved branch of ER stress and the UPR (unfolded protein response), is a key regulator of de novo uridine synthesis via upregulation of Cad expression. Hepatocyte overexpression of XBP1s leads to hypoglycemia and lipolysis. Taken together, our study uncovers a novel link of uridine homeostasis and hepatic glycemic control through cellular response to ER stress, which provides potential targets for therapeutic design against obesity and T2D. Supported by the American Diabetes Association and NIDDK. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Published Version
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