The hepatic BMAL1/AKT/lipogenesis axis protects against alcoholic liver disease in mice via promoting PPARα pathway.

Alcohol liver disease (ALD) is one of the major chronic liver diseases worldwide, ranging from fatty liver, alcoholic hepatitis, cirrhosis, and potentially, hepatocellular carcinoma. Epidemiological studies suggest a potential link between ALD and impaired circadian rhythms, but the role of hepatic circadian proteins in the pathogenesis of ALD remains unknown. Here we show that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect mice from ALD. Ethanol diet-fed mice with liver-specific knockout (Bmal1-LKO) or depletion of Bmal1 develop more severe liver steatosis and injury as well as a simultaneous suppression of both de novo lipogenesis and fatty acid oxidation, which can be rescued by the supplementation of synthetic PPARα ligands. Restoring de novo lipogenesis in the liver of Bmal1-LKO mice by constitutively active AKT not only elevates hepatic fatty acid oxidation but also alleviates ethanol-induced fatty liver and liver injury. Furthermore, hepatic over-expression of lipogenic transcription factor ChREBP, but not SREBP-1c, in the liver of Bmal1-LKO mice also increases fatty acid oxidation and partially reduces ethanol-induced fatty liver and liver injury. Conclusion: we identified a protective role of BMAL1 in hepatocytes against ALD. The protective action of BMAL1 during alcohol consumption depends on its ability to couple ChREBP-induced de novo lipogenesis with PPARα-mediated fatty oxidation. (Hepatology 2018).

Morphological characteristics of subchondral bone cysts in medial femoral condyles of adult horses as determined by computed tomography.

OBJECTIVE: To determine morphological characteristics of subchondral bone cysts (SBCs) in medial femoral condyles (MFCs) of adult horses with orthopedic disease. SAMPLE: CT scans of 7 MFCs with SBCs from 6 adult horses. PROCEDURES: CT was used to determine the volume, surface area, and centers of the articular cyst opening and SBC in each MFC. Cysts were ordered from smallest to largest on the basis of volume. Osseous pathological characteristics of the MFC were assessed in the frontal plane. Three-dimensional distance of displacement between the center of the articular cyst opening and center of the cyst was determined for each SBC. Cyst surface area-to-volume ratio was evaluated and compared with that of a true sphere. RESULTS: All SBCs had a defect in the subchondral bone plate at the cranial 15% to 20% of the MFC. Cyst center was located in a caudal, proximal, and abaxial direction with respect to the center of the articular cyst opening for each horse. Small- and intermediate-volume SBCs were irregular and multilobulated, whereas large-volume SBCs were smooth and discrete with a surface area-to-volume ratio approaching that of a sphere. CONCLUSIONS AND CLINICAL RELEVANCE: Consistency in morphological characteristics suggested a common etiopathogenesis for SBCs in MFCs of adult horses. Cyst enlargement may have been attributable to a biomechanical predisposition to decrease the surface area-to-volume ratio, resulting in a spherical cyst.

Intussusception in horses.

Intussusception is thought to be associated with abnormal motility in the intestinal tract. The clinical signs vary depending on the associated intestinal damage. Therefore, intussusception should be included in the differential diagnosis for any horse with acute or chronic colic. A diagnosis may be made by ultrasonography or rectal palpation, but exploratory laparotomy is the predominant method. Treatment varies according to the location of the intussusception, but all treatments involve surgical intervention. The prognosis for intussusception can be good if the condition is diagnosed and treated promptly.

Organellar proteomics: analysis of pancreatic zymogen granule membranes.

The zymogen granule (ZG) is the specialized organelle in pancreatic acinar cells for digestive enzyme storage and regulated secretion and has been a model for studying secretory granule functions. In an initial effort to comprehensively understand the functions of this organelle, we conducted a proteomic study to identify proteins from highly purified ZG membranes. By combining two-dimensional gel electrophoresis and two-dimensional LC with tandem mass spectrometry, 101 proteins were identified from purified ZG membranes including 28 known ZG proteins and 73 previously unknown proteins, including SNAP29, Rab27B, Rab11A, Rab6, Rap1, and myosin Vc. Moreover several hypothetical proteins were identified that represent potential novel proteins. The ZG localization of nine of these proteins was further confirmed by immunocytochemistry. To distinguish intrinsic membrane proteins from soluble and peripheral membrane proteins, a quantitative proteomic strategy was used to measure the enrichment of intrinsic membrane proteins through the purification process. The iTRAQ ratios correlated well with known or Transmembrane Hidden Markov Model-predicted soluble or membrane proteins. By combining subcellular fractionation with high resolution separation and comprehensive identification of proteins, we have begun to elucidate zymogen granule functions through proteomic and subsequent functional analysis of its membrane components.