2.2 Specific distribution of HNF4α isoforms in organs and tissues
As describe above, the structural differences among HNF4α isoforms have raised the hypothesis that distinct functions related to these differences might occur in the context of co-interacting partners in transcriptional regulation during embryonic development and adult organ tissue maintenance [22]. Numerous studies have evaluated the differential expression of HNF4α isoforms in a variety of tissues, with the general observation that expression of HNF4α is predominant in the liver, small intestine, colon, and kidneys [6, 27, 30, 34, 35, 37, 39] and to a lesser extent, in the stomach, pancreas, testes, bladder, prostate, ovaries, heart, spleen, lungs, skin, and skeletal muscles [31, 32, 39]. The initial development of specific antibodies for P1 and P2 classes of isoforms has allowed clarifying this profile of expression at the protein level. In the liver, it was observed that P2 isoforms (α7 to α9) are co-expressed with P1 isoforms (α1 to α6) during embryonical stages, while only P1 isoforms become detectable in the adult phase [40]. In healthy renal tissues, P1 isoforms expression was also found to be much higher than P2 isoforms expression, while adult pancreatic and gastric tissues showed a much higher level of expression of P2 isoforms than P1 isoforms [39]. While the intestine displays a higher expression of P2 isoforms at the embryonical stage, it appears that this is the only organ at the adult stage able to express comparable levels of both P1 and P2 isoforms [39]. However, the lack of specific antibodies able to discriminate between the specific isoforms that compose both HNF4α P1 and P2 family members in these physiological contexts still prevent the scientific community from further pinpointing these expression profiles.
For this reason, many groups have turned to the use of techniques allowing the measurement of specific gene transcripts for some of these specific isoforms. For example, HNF4α1 (P1a-α1) was found to be much more abundant than both HNF4α2 and HNF4α3 (P1a-α3) isoforms in both the liver and kidneys [27, 36]. Although the existence of P1b-α4 to P1b-α6 isoforms is still controversial based on expression studies, a recent report has suggested these isoforms harbor potent repression activity for the regulation of liver-specific genes and, at the same time, participate in the activation of genes involved in the pro-inflammatory response [32]. P2a-α7 and P2a-α8 isoforms in adult pancreatic tissues are much more expressed than P2a-α9 and P2b-α10 to P2b-α12. More particularly, P2a-α9 isoform is less expressed in the islets of Langerhans than in the rest of the pancreas, whereas P1a-α1 to P1a-α3 isoforms are only detected in the embryonic tissue. However, both P1a-α1 and P1a-α2 isoforms have been reported to be expressed in adult mouse islets of Langerhans [30, 41-44]. In the digestive tract, expression of the HNF4α isoforms vary according to the region studied. In the stomach, higher expression of both P1a-α1[44] and P2a-α7 [45] isoforms was reported. In contrast, expression of P1a-α2, P2a-α7, P2a-α8, and P2a-α9 was more critical from the duodenum to the rectum, with some expression of P1a-α1 in the regional portions of the colon [31]. P1b-α4, P1b-α5, P1b-α6, and P2b-α10 [32] were also reported expressed in the small intestine and colon, while P2b-α12 isoform was strictly detected in the small intestine [32]. It is noteworthy to mention that no expression for any HNF4α isoforms has never been detected in the esophagus [31].