Livers of hyperglycemic mice with Hnf1a-deficient pancreatic beta-cells show unexpected hepatic steatosis signs further exacerbated by high fat diet

Background In the past decades tissue/cell targeted single gene modifications using transgenic systems became a main-stream practice aimed at demultiplexing tissue- and cell-specific gene function. Yet, targeting of many genes and cell types can cause systemic effects, impacting the functionality of other off-target organs. This can further generate a discrete dysfunction loop fueling back to the targeted cell altering their profile readout, effect demultiplexing and results interpretation. Despite the high impact of such scenario especially in the study of endocrine organs, most research is focused on targeted mutation-bearing cell population, while the other organs bearing intact candidate gene activity, receive no or limited attention. Results To assess the potential readout bias caused by off-target organs, we performed here a focused pilot transcriptomics study to map the effects on liver of a monogenic diabetes gene mutation restricted to insulin-expressing beta-cells. Mice with beta-cell restricted disfunction were mildly hyperglycemic and presented normal target gene levels in the liver. Despite normal expression, pathway analyses identified profound transcriptional prolife changes in the liver. These involved the dysregulation of lipid metabolism and extracellular matrix organization, cholesterol biosynthesis being further exacerbated by HFD, consistent with a systemic factor effect such as chronically elevated blood sugar levels. Furthermore, key markers of hepatic steatosis were highly increased, with the livers’ histopathology reflecting lipid droplet accumulation. As hepatic steatosis is an important cause of hepatic insulin resistance that can further alter beta-cell function, the interpretation of the transcriptional background in the targeted beta-cell population must be performed with care. Conclusions Based on this pilot we conclude that multi-organ dysfunction loops can drastically change the read-out in the mutated cell complicating the effect separation. Thus investigating off-target organs is crucial, especially when characterizing genes and cell populations involved in endocrine regulation.