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Reverse cholesterol transport (RCT) and transintestinal cholesterol efflux (TICE) are two important pathways for body cholesterol elimination. We studied these pathways in an animal model of diabetes and obesity (ob/ob) where HDL function is compromised as a result of hyperglycemia, low-grade inflammation and oxidative stress. Co-treatment of ob/ob mice with PPAR-α (fenofibrate) and LXR (T0901317) agonists increased fecal cholesterol by 12-fold; PPAR-α and LXR agonists individually showed 2.6- and 4.0-fold fecal cholesterol excretion, respectively. We investigated the mechanism of synergistic efficacy of PPAR-α and LXR agonists in fecal cholesterol excretion. LXR agonist and the combination of PPAR-α and LXR agonists had greater HDL-C elevation. Ex vivo cholesterol efflux showed correlation with the fecal cholesterol excretion but was not sufficient to explain 12-fold increases in the fecal cholesterol in the co-treated mice. Therefore, we examined TICE to explain the 12-fold increases in the fecal cholesterol. A strong positive correlation of fecal cholesterol with ATP binding cassette transporter G5 (ABCG5) and G8 and a negative correlation with NPC1L1 was observed. ABCG5, G8 and NPC1L1 are involved in intestinal cholesterol absorption. The extent of influence of PPAR-α and LXR agonists on RCT and TICE was distinctly different. PPAR-α agonist increased fecal cholesterol primarily by influencing TICE, while LXR agonist influenced fecal cholesterol excretion via both RCT and TICE mechanisms. Synergistic efficacy on fecal cholesterol excretion following co-treatment with PPAR-α and LXR agonists occurred through a combination of RCT, TICE, and the key enzyme in bile synthesis, cholesterol 7-α hydroxylase (cyp7a1). These results suggest that cholesterol efflux, biliary cholesterol excretion, and TICE collectively contributed to the 12-fold increases in the fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists. [ABSTRACT FROM AUTHOR]

Liquefaction-induced ground failure is one amongst the leading causes of infrastructure damage due to the impact of large earthquakes in unconsolidated, non-cohesive, water saturated alluvial terrains. The city of Kolkata is located on the potentially liquefiable alluvial fan deposits of Ganga-Bramhaputra-Meghna Delta system with subsurface litho-stratigraphic sequence comprising of varying percentages of clay, cohesionless silt, sand, and gravel interbedded with decomposed wood and peat. Additionally, the region has moderately shallow groundwater condition especially in the post-monsoon seasons. In view of burgeoning population, there had been unplanned expansion of settlements in the hazardous geological, geomorphological, and hydrological conditions exposing the city to severe liquefaction hazard. The 1897 Shillong and 1934 Bihar-Nepal earthquakes both of M 8.1 reportedly induced Modified Mercalli Intensity of IV-V and VI-VII respectively in the city reportedly triggering widespread to sporadic liquefaction condition with surface manifestation of sand boils, lateral spreading, ground subsidence, etc., thus posing a strong case for liquefaction potential analysis in the terrain. With the motivation of assessing seismic hazard, vulnerability, and risk of the city of Kolkata through a consorted federal funding stipulated for all the metros and upstart urban centers in India located in BIS seismic zones III, IV, and V with population more than one million, an attempt has been made here to understand the liquefaction susceptibility condition of Kolkata under the impact of earthquake loading employing modern multivariate techniques and also to predict deterministic liquefaction scenario of the city in the event of a probabilistic seismic hazard condition with 10% probability of exceedance in 50 years and a return period of 475 years. We conducted in-depth geophysical and geotechnical investigations in the city encompassing 435 km area. The stochastically synthesized bedrock ground motion for both the 1897 and 1934 earthquakes on non-linear analysis of local site conditions through DEEPSOIL Geotechnical analysis package present surface level peak ground acceleration of the order of 0.05-0.14 g for the 1934 Bihar-Nepal earthquake while for the 1897 Shillong earthquake it is found to be in the range of 0.03-0.11 g. The factor of safety (FOS) against liquefaction, the probability of liquefaction ( P ), the liquefaction potential index (LPI), and the liquefaction risk index are estimated under the influence of these two earthquakes wherein the city is classified into severe (LPI > 15), high (5 < LPI ≤ 15), moderate (0 < LPI ≤ 5), and non-liquefiable (LPI = 0) susceptibility zones. While the 1934 Bihar-Nepal earthquake induced moderate to severe liquefaction hazard condition in the city in mostly the deltaic plain and interdistributary marsh geomorphologic units with 13.5% sites exhibiting moderate hazard with a median LPI of 1.8, 8.5% sites depicting high with a median LPI of 9.1 and 4% sites with a median LPI of 18.9 exhibiting severe hazard condition, 1897 Shillong earthquake induced mostly non-liquefaction condition with very few sites depicting moderate and high liquefaction hazard. A conservative liquefaction hazard scenario of the city on the other hand estimated through deterministic approach for 10% probability of exceedance in 50 years predicts a high hazard zone in the 3.5-19 m depth region with FOS < 1 and P > 65% comprising of coarse-grained sediments of sand, silty sand, and clayey silty sand in mostly the deltaic plain geomorphologic unit with 39.1% sites depicting severe liquefaction hazard with a median LPI of 28.3. A non-linear regression analysis on both the historical and deterministic liquefaction scenarios in P versus LPI domain with ± 1 standard deviation confidence bound generated a cubic polynomial relationship between the two liquefaction hazard proxies. This study considered a bench mark for other cities in the country and elsewhere forms an integral part of the mega-seismic microzonation endeavors undertaken in all the earthquake-prone counties in the world. [ABSTRACT FROM AUTHOR]