Since domestication, pigs have been used extensively in agriculture and kept as companion animals. More recently they have been used in biomedical research, given they share many physiological and anatomical similarities with humans. Recent technological advances in assisted reproduction, somatic cell cloning, stem cell culture, genome editing and transgenesis now enable the creation of unique porcine models of human diseases. Here we highlight the potential applications and advantages of using pigs, particularly minipigs, as indispensable large animal models in fundamental and clinical research, including the development of therapeutics for inherited and chronic disorders, and cancers.

Endoplasmic reticulum (ER) stress has been linked to many diseases, including cancer. A large body of work has focused on the activation of the ER stress response in cancer cells to facilitate their survival and tumor growth; however, there are some studies suggesting that the ER stress response can also mitigate cancer progression. Despite these contradictions, it is clear that the ER stress response is closely associated with cancer biology. The ER stress response classically encompasses activation of three separate pathways, which are collectively categorized the unfolded protein response (UPR). The UPR has been extensively studied in various cancers and appears to confer a selective advantage to tumor cells to facilitate their enhanced growth and resistance to anti-cancer agents. It has also been shown that ER stress induces chromatin changes, which can also facilitate cell survival. Chromatin remodeling has been linked with many cancers through repression of tumor suppressor and apoptosis genes. Interplay between the classic UPR and genome damage repair mechanisms may have important implications in the transformation process of normal cells into cancer cells.

Nutrition transition, which includes a change from consumption of traditional to modern diets that feature high-energy density and low nutrient diversity, is associated with acquired metabolic syndromes. The human diet is comprised of diverse components which include both nutrients, supplying the raw materials that drive multiple metabolic processes in every cell of the body, and non-nutrients. These components and their metabolites can also regulate gene expression and cellular function via a variety of mechanisms. Some of these components are beneficial while others have toxic effects. Studies have found that persistent disturbance of nutrient metabolism and/or energy homeostasis, caused by either nutrient deficiency or excess, induces cellular stress leading to metabolic dysregulation and tissue damage, and eventually to development of acquired metabolic syndromes. It is now evident that metabolism is influenced by extrinsic factors (e.g., food, xenobiotics, environment), intrinsic factors (e.g., sex, age, gene variations) as well as host/microbiota interaction, that together modify the risk for developing various acquired metabolic diseases. It is also becoming apparent that intake of diets with low-energy density but high in nutrient diversity may be the key to promoting and maintaining optimal health.

The ileal lipid binding protein (ilbp) is a cytoplasmic protein that binds bile acids with high affinity. However evidence demonstrating the role of this protein in bile acid transport and homeostasis is missing. We created a mouse strain lacking ilbp (Fabp6^−/− mice) and assessed the impact of ilbp deficiency on bile acid homeostasis and transport in vivo. Elimination of ilbp increased fecal bile acid excretion (54.2%, P<0.05) in female but not male Fabp6^−/− mice. The activity of cholesterol 7α-hydroxylase (cyp7a1), the rate-controlling enzyme of the classical bile acid biosynthetic pathway, was significantly increased in female (63.5%, P<0.05) but not in male Fabp6^−/− mice. The amount of [³H]taurocholic acid (TCA) excreted by 24 h after oral administration was 102% (P<0.025) higher for female Fabp6^−/− mice whereas it was 57.3% (P<0.01) lower for male Fabp6^−/− mice, compared to wild-type mice. The retained fraction of the [³H]TCA localized in the small and large intestines was increased by 22% (P<0.02) and decreased by 62.7% (P<0.01), respectively, in male Fabp6^−/− mice relative wild-type mice, whereas no changes were seen in female Fabp6^−/− mice. Mucosal to serosal bile acid transport using everted distal gut sacs was decreased by 74% (P<0.03) in both sexes of Fabp6^−/− mice as compared to wild-type mice. The results demonstrate that ilbp is involved in the apical to basolateral transport of bile acids in ileal enterocytes, and is vital for the maintenance of bile acid homeostasis in the enterohepatic circulation (EHC) in mice.