High-density lipoprotein metabolism in human apolipoprotein B₁₀₀transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

Abstract

Obese and diabetic humans display decreased plasma high-density lipoprotein cholesterol (HDL-C) concentrations and an increased risk for coronary heart disease. However, investigation on HDL metabolism in obesity with a particular emphasis on hepatic ATP-binding cassette transporter A1 (ABCA1), the primary factor for HDL formation, has not been well studied. Human apolipoprotein B100 transgenic (hApoB tg ) and brown adipose tissue deficient (BATless) mice were crossed to generate hApoB tg /BATless mice. Male and female hApoB tg and hApoB tg /BATless mice were maintained on either a regular rodent chow diet or a diet high in fat and cholesterol until 24 weeks of age. The hApoB tg /BATless mice that were fed a HF/HC diet became obese, developed hepatic steatosis, and had significantly elevated plasma insulin levels compared with their hApoB tg counterparts, but plasma concentrations of total cholesterol, HDL-C, triglycerides, and free fatty acids and lipoprotein distribution between genotypes were not significantly different. Hepatic expression of genes encoding HDL-modifying factors (e.g., scavenger receptor, class B, type I, hepatic lipase, lecithin:cholesterol acyltransferase, and phospholipid transfer protein) was either altered significantly or showed a trend 3 6 (2 0 1 1 ) 2 of difference between 2 genotypes of mice. Importantly, hepatic protein levels of ABCA1 were significantly lowered by ∼35% in male obese hApoB tg /BATless mice with no difference in mRNA levels compared with hApoB tg counterparts. Despite reduced hepatic ABCA1 protein levels, plasma HDL-C concentrations were not altered in male obese hApoB tg /BATless mice. The result suggests that hepatic ABCA1 may not be a primary contributing factor for perturbations in HDL metabolism in obesityinduced hyperinsulinemia. , A P P L I E D P H Y S I O L O G Y , N U T R I T I O N , A N D M E T A B O L I S M

Long‐Term Supplementation of Black Elderberries Promotes Hyperlipidemia, but Reduces Liver Inflammation and Improves HDL Function and Atherosclerotic Plaque Stability in Apolipoprotein E‐Knockout Mice

“…Indirect sandwich ELISAs were performed for apoA‐I (Fine Biological Technology; Whuan, China), SAA (R&D Systems; Minneapolis, MN), monocyte chemoattractant protein‐1 (MCP‐1) (R&D Systems; Minneapolis, MN), PON1 (Bosterbio; Pleasanton, CA), and tumor necrosis factor alpha (TNF‐α) (eBioscience; Vienna, Austria). Pooled serum samples were fractionated by fast protein liquid chromatography (FPLC) to evaluate lipoprotein cholesterol distribution using methods previously reported …”

Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis

“…Overproduction of large VLDL 1 is driven by increased flux of nonesterified fatty acids from adipose tissue, upregulation of sterol regulatory element binding protein-1c (SREBP-1c), chronic stimulation of de novo lipogenesis, and reduced fatty acid oxidation in the liver [1][2][3][4]. Circulating HDL levels are maintained by hepatic ABCA1 [5], insulin resistance causes loss of hepatic ABCA1 protein expression [5][6][7][8][9] and a strong reciprocal relationship exists between ABCA1 expression and hepatic VLDL output [10][11][12][13], integrating triglyceride and cholesterol lipoprotein metabolism. Dysregulated hepatic lipid metabolism also contributes to non-alcoholic fatty liver disease (NAFLD), present in 70-80% of diabetic and obese patients [14], and a condition which ranges from simple steatosis (SS) to steatosis combined with necrosis and inflammation (non-alcoholic steatohepatitis; NASH) which can progress to hepatic fibrosis and cirrhosis [14][15][16][17][18].…”

Effect of combined mulberry leaf and fruit extract on liver and skin cholesterol transporters in high fat diet-induced obese mice

“…Some research reported that dietary supplement of Curcumin with moderated intake of alcohol increased cholesterol efflux mediated by ABCA1 [20,21]. However, according to a recent study, hepatic ABCA1 may not be the main contributing factor of HDL metabolism in a model of obesity-induced hyperinsulinemia using human apolipopretein B100 transgenic/brown adipose tissue deficient mice [22]. Thus, there is still controversy about the role of ABCA1 in regulating the HDL-cholesterol level.…”