The HSPA5 gene (Ensembl ID: ENSG00000044574 (WTSI/EMBL-EBI, 2015)) encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen. As a highly conserved molecular chaperone, BiP assists in a wide range of folding processes via its two structural domains, a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). BiP is also an essential component of the translocation machinery for protein import into the ER, a regulator for Ca2+ homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane. When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. Post- translational modifications (PTMs) of BiP have been shown to regulate BiP’s activity, turnover, and availability upon different extrinsic or intrinsic stimuli. As a master regulator of ER function, BiP is associated with cancer, cardiovascular disease, neurodegenerative disease, and immunological diseases. BiP has been targeted in cancer therapies and shows promise for application in other relevant diseases.

The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2–deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2–deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2–deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.

We identified a mutation in the Diet1 gene in a mouse strain that is resistant to hyperlipidemia and atherosclerosis. Diet1 encodes a 236 kD protein consisting of tandem low density lipoprotein receptor and MAM (meprin-A5-protein tyrosine phosphatase mu) domains, and is expressed in enterocytes of the small intestine. Diet1-deficient mice exhibited an elevated bile acid pool size and impaired feedback regulation of hepatic Cyp7a1, which encodes the rate-limiting enzyme in bile acid synthesis. In mouse intestine and in cultured human intestinal cells, Diet1 expression levels influenced the production of fibroblast growth factor 15/19 (FGF15/19), a hormone that signals from the intestine to liver to regulate Cyp7a1. Transgenic expression of Diet1, or adenoviral-mediated Fgf15 expression, restored normal Cyp7a1 regulation in Diet-1–deficient mice. Diet1 and FGF19 proteins exhibited overlapping subcellular localization in cultured intestinal cells. These results establish Diet1 as a control point in enterohepatic bile acid signaling and lipid homeostasis.

Opioid administration with significant accompanying hypercarbia and hypoxia results in pupil diameters of 2 to 3 mm and a reduced but quantifiable pupillary light reflex. The authors conclude that the pupillary examination and evaluation of the light reflex remain useful for neurologic assessment during opioid toxicity.