Kai Su

University of Kentucky, Lexington, Kentucky, United States

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Publications (5)24.27 Total impact

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    ABSTRACT: Objective: Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant, and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic G5G8. Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanisms responsible for G5G8 regulation remain unclear. In the current study, we used a series of mouse models to address potential mechanisms for leptin-mediated regulation of G5G8. Methods and results: We acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, G5G8 may be decreased in ob/ob and db/db mice due to ER dysfunction, the site of G5G8 complex assembly. Overexpression of the ER chaperone GRP78 using an adenoviral vector restores ER function and reduces steatosis in ob/ob mice. Therefore, we determined if AdGRP78 could rescue G5G8 in db/db mice. As in ob/ob mice, AdGRP78 reduced expression of lipogenic genes and plasma triglycerides in the db/db strain. Both G5 and G8 protein levels increased as did total biliary cholesterol, but in the absence of changes in G5 or G8 mRNAs. The increase in G5G8 was associated with increases in a number of proteins, including the ER lectin chaperone, calnexin, a key regulator of G5G8 complex assembly. Conclusions: Leptin signaling does not directly regulate G5G8 abundance. The loss of G5G8 in mice harboring defects in the leptin axis is likely associated with compromised ER function.
    No preview · Article · Sep 2015 · Metabolism: clinical and experimental
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    ABSTRACT: Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice. Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (adenoviruses encoding G5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. Adenoviruses encoding G5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period. Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.
    Preview · Article · Nov 2013 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: ABCG5 and ABCG8 form a complex (G5G8) that opposes the absorption of plant sterols but is also expressed in liver where it promotes the excretion of cholesterol into bile. Hepatic G5G8 is transcriptionally regulated by a number of factors implicated in the development of insulin resistance and nonalcoholic fatty liver disease. Therefore, we hypothesized that G5G8 may influence the development of diet-induced obesity phenotypes independently of its role in opposing phytosterol absorption. G5G8 knock-out (KO) mice and their wild type (WT) littermates were challenged with a plant sterol-free low fat or high fat (HF) diet. Weight gain and the rise in fasting glucose were accelerated in G5G8 KO mice following HF feeding. HF-fed G5G8 KO mice had increased liver weight, hepatic lipids, and plasma alanine aminotransferase compared with WT controls. Consistent with the development of nonalcoholic fatty liver disease, macrophage infiltration, the number of TUNEL-positive cells, and the expression of proinflammatory cytokines were also increased in G5G8 KO mice. Hepatic lipid accumulation was associated with increased peroxisome proliferator activated receptor γ, CD36, and fatty acid uptake. Phosphorylation of eukaryotic translation initiation factor 2α (eiF2α) and expression of activating transcription factor 4 and tribbles 3 were elevated in HF-fed G5G8 KO mice, a pathway that links the unfolded protein response to the development of insulin resistance through inhibition of protein kinase B (Akt) phosphorylation. Phosphorylation of Akt and insulin receptor was reduced, whereas serine phosphorylation of insulin receptor substrate 1 was elevated.
    Preview · Article · Jun 2012 · Journal of Biological Chemistry

  • No preview · Conference Paper · Nov 2010
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    ABSTRACT: Lactation is associated with increased expression of bile acid transporters and an increased size and hydrophobicity of the bile acid pool in rats. ATP-binding cassette (ABC) transporters multidrug resistance protein 2 (Mdr2), Abcb11 [bile salt export pump (Bsep)], and Abcg5/Abcg8 heterodimers are essential for the biliary secretion of phospholipids, bile acids, and cholesterol, respectively. We investigated the expression of these transporters and secretion of their substrates in female control and lactating Sprague Dawley rats and C57BL/6 mice. Expression of Abcg5/Abcg8 mRNA was decreased by 97 and 60% by midlactation in rats and mice, respectively; protein levels of Abcg8 were below detection limits in lactating rats. Mdr2 mRNA expression was decreased in lactating rats and mice by 47 and 59%, respectively. Despite these changes in transporter expression, basal concentrations of cholesterol and phospholipid in bile were unchanged in rats and mice, whereas increased Bsep mRNA expression in early lactation coincided with an increased basal biliary bile acid concentration in lactating mice. Following taurocholate infusion, coupling of phospholipid and taurocholate secretion in bile of lactating mice was significantly impaired relative to control mice, with no significant changes in maximal secretion of cholesterol or bile acids. In rats, taurocholate infusion revealed a significantly impaired coupling of cholesterol to taurocholate secretion in bile in lactating vs. control animals. These data reveal marked utilization of an Abcg5/Abcg8-independent mechanism for basal biliary cholesterol secretion in rats during lactation, but a dependence on Abcg5/g8 for maximal biliary cholesterol secretion.
    Preview · Article · Apr 2010 · AJP Gastrointestinal and Liver Physiology