Commentary
Abstract
Bile acids are natural detergents that assist in the absorption and digestion of fats in the intestine. In liver, the synthesis of bile acids from cholesterol is regulated by multiple signaling cascades that repress transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the classic bile acid synthesis pathway. In this issue of the JCI, Ito and coworkers demonstrate that mice lacking βKlotho, a membrane protein with 2 putative glycosidase domains, have increased Cyp7a1 mRNA levels and bile acid concentrations. βKlotho-KO mice also have small gallbladders and are resistant to cholesterol gallstone formation. These findings highlight the central role of βKlotho in bile acid homeostasis and raise the possibility that this protein could be a pharmacologic target for the treatment of gallstones.
Authors
Antonio Moschetta, Steven A. Kliewer
Abstract
The distinction between peptides that bind to class II MHC products under laboratory conditions and those that do so physiologically is important for the prediction of antigens recognized by autoreactive T cells. In this issue of the JCI, Suri et al., using antigen-presenting cells, compared the peptides that bound to human HLA-DQ8 and those that bound to mouse I-Ag7, both class II MHC products that predispose their carriers to type 1 diabetes. The rules of engagement for the peptide ligands of the DQ8 and I-Ag7 molecules involve similarities in their anchor residues, which mediate stable interaction with class II MHC products. The peptides identified derive from overlapping sets of self proteins.
Authors
Hidde L. Ploegh
Abstract
Recently, mutations causing juvenile hemochromatosis have been identified in a novel gene, hemojuvelin (HJV), located on chromosome 1. Mouse models of this disease have now been developed by 2 groups, Huang et al. and Niederkofler et al., through targeted disruption of the Hjv gene (see the related articles beginning on pages 2180 and 2187). These mutant mice will allow further investigation into the role of HJV in the regulation of iron homeostasis, a role that to date remains elusive.
Authors
Sophie Vaulont, Dan-Qing Lou, Lydie Viatte, Axel Kahn
Abstract
In order to examine the factors governing the timing and flexibility of skeletal muscle switching between fat and carbohydrate oxidation, Ukropcova et al. studied the effect of glucose and fatty acid availability on the preference for fat oxidation in myocytes cultured from human male quadriceps muscle taken from subjects with varied BMI, fat mass, and insulin sensitivity. The authors found that in vivo insulin sensitivity was related to a higher in vitro capacity for fat oxidation. These findings support the concept that the capacity of skeletal muscle to oxidize fat under appropriate physiological conditions is related to leanness, aerobic fitness, and insulin sensitivity.
Authors
David E. Kelley
Abstract
In the days following infection, when the human body develops and refines antibodies and prepares to mount an adaptive immune response, the bulwark of innate host defense against microbial infection is the polymorphonuclear leukocyte (PMN). PMNs seek out, identify, engulf, and sterilize invading microbes using both O2-dependent and O2-independent antimicrobial systems. A decrease in PMN numbers or function caused by immunosuppression or disease increases the risk of infection. In this issue of the JCI, Peyssonnaux et al. identify a novel and essential role for hypoxia-inducible factor–1α in regulating several important PMN functions relevant to host defense, including transcription of cationic antimicrobial polypeptides and induction of NO synthase.
Authors
Kol A. Zarember, Harry L. Malech
Abstract
Epithelial organs such as the intestine and skin have a relatively high rate of cell loss and thus require a reservoir of stem cells capable of both replacing the lost epithelia and maintaining the reservoir. Whether the kidney has such a stem cell niche has been a subject of great interest; the majority of data suggest that replacement of renal epithelial cells occurs via dedifferentiation and proliferation of existing tubular cells, while some studies demonstrate the presence of potential tubular stem cells in the renal interstitium. However, recent reports have suggested that the bone marrow may also be a source of stem cells for tubule turnover and/or repair. In this issue of the JCI, 2 groups explore the role of endogenous cells versus bone marrow–derived cells in mediating tubule repair. Duffield and colleagues demonstrate that bone marrow does contain cells capable of protecting the kidney from ischemic injury, but found that these cells do not act by direct incorporation into the repaired tubular segments. In contrast, Lin and coworkers found that some bone marrow–derived cells do appear to incorporate into the injured tubule as epithelial cells (see the related article beginning on page 1756). Importantly, both groups conclude that the majority of tubule repair occurs via proliferation of endogenous renal cells rather than incorporation of bone marrow–derived cells.
Authors
Diane Krause, Lloyd G. Cantley
Abstract
Harlequin ichthyosis (HI) — the most severe form of keratinizing disorders, often lethal in the neonatal period — is characterized by a profound thickening of the keratin skin layer, a dense “armor”-like scale that covers the body, and contraction abnormalities of the eyes, ears, and mouth. In this issue of the JCI, Akiyama et al. report that mutations in ABCA12 caused defective lipid transport that significantly impacted normal development of the skin barrier. Lipid secretion was recovered after corrective ABCA12 gene transfer into patient keratinocytes. These results should allow for early prenatal diagnosis of HI and lend hope to the possibility of a specific treatment for this devastating disorder.
Authors
Alain Hovnanian
Abstract
Chromogranin A (CHGA) and its derived peptides, which are stored and released from dense-core secretory granules of neuroendocrine cells, have been implicated as playing multiple roles in the endocrine, cardiovascular, and nervous systems. In this issue of the JCI, Mahapatra et al. present in vivo evidence for 2 important functions of CHGA: the regulation of catecholamine-containing dense-core chromaffin granule biogenesis in the adrenal gland and the control of blood pressure. Obliteration of CHGA expression in a KO mouse model led to decreased size and number of chromaffin granules as well as hypertension in these animals. Transgenic expression of human Chga and exogenous injection of human catestatin, a CHGA-derived nicotinic cholinergic antagonist, restored normal blood pressure in these mice. These results suggest a coupled relationship between CHGA-mediated chromaffin granule biogenesis, necessary for catecholamine storage, and catestatin-induced inhibition of cholinergic-stimulated catecholamine release, which regulates autonomic control of blood pressure.
Authors
Taeyoon Kim, Y. Peng Loh
Abstract
Atrial natriuretic peptide (ANP) acts acutely to reduce plasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular permeability. Authors of a study in this issue of the JCI performed a knockout of the receptor for ANP in vascular endothelia in order to distinguish the effects of ANP-dependent increases in vascular permeability from those of other endocrine actions of ANP in the regulation of plasma volume. The knockout mice exhibited reduced vascular permeability to plasma protein, resulting in chronically increased plasma volume, arterial hypertension, and cardiac hypertrophy. Renal excretion and vasodilation did not account for these changes. Thus ANP-induced increases in endothelial permeability may be critical to the ability of ANP to lower arterial blood pressure.
Authors
Fitz-Roy E. Curry
Abstract
Hyperplasia of pulmonary artery SMCs (PASMCs) is a pathological hallmark of pulmonary arterial hypertension (PAH). In this issue of the JCI, McMurtry et al. report that adenovirus-mediated overexpression of survivin — a multipotent inhibitor of apoptosis — induces PAH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative properties reverses established monocrotaline-induced PAH. These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies.
Authors
Serge Adnot
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