Accelerated fatty acid oxidation in muscle averts fasting-induced hepatic steatosis in SJL/J mice.
ABSTRACT The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced hepatic steatosis is under genetic control in inbred mice. After a 24-h fast, C57BL/6J mice and SJL/J mice both lost more than 20% of body weight and approximately 60% of total body TG. In C57BL/6J mice, TG accumulated in liver, producing frank steatosis. In striking contrast, SJL/J mice failed to accumulate any hepatic TG even though they lost nearly as much adipose tissue mass as the C57BL/6J mice. Mice from five other inbred strains developed fasting-induced steatosis like the C57BL/6J mice. Measurements of the uptake of free fatty acids (FA) in vivo and in vitro demonstrated that SJL/J mice were protected from steatosis because their heart and skeletal muscle took up and oxidized twice as much FA as compared with C57BL/6J mice. As a result of this muscle diversion, serum-free FA and ketone bodies rose much less after fasting in SJL/J mice as compared with C57BL/6J mice. When livers of SJL/J and C57BL/6J mice were perfused with similar concentrations of FA, the livers took up and esterified similar amounts. We conclude that SJL/J mice express one or more variant genes that lead to enhanced FA uptake and oxidation in muscle, thereby sparing the liver from FA overload in the fasting state.
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ABSTRACT: To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body β-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype. Radiotracer analysis confirms that loss of Slc16a6a function causes diversion of liver-trapped ketogenic precursors into triacylglycerol. Underscoring the importance of Slc16a6a to normal fasting physiology, previously fed rmn mutants are more sensitive to death by starvation than are wild-type larvae. Our unbiased, forward genetic approach has found a heretofore unrecognized critical step in fasting energy metabolism: hepatic ketone body transport. Since β-hydroxybutyrate is both a major fuel and a signaling molecule in fasting, the discovery of this transporter provides a new direction for modulating circulating levels of ketone bodies in metabolic diseases.Genes & development 02/2012; 26(3):282-93. DOI:10.1101/gad.180968.111 · 12.64 Impact Factor
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ABSTRACT: Rodents are commonly used in food restriction refeeding studies to investigate weight regain. Mice that are rationed food every 24h may consume all allocated food in a short time (gorge) and therefore undergo a brief well-fed period followed by an extended fasted period until the next day's food allotment. These exaggerated metabolic states are not typical in mice fed ad libitum (nibbling). The aim of the current study was to elucidate the intraday and cumulative metabolic consequences of gorging (induced by food restriction) in mice during controlled refeeding. Accordingly, following a temporary food restriction, mice were fed rations similar to intakes of controls fed ad libitum. Temporary food restriction initiated gorging behavior that persisted during refeeding; consequently, metabolism-related measurements were obtained in the gorging mice during their daily fed and fasted metabolic states. Robust differences in adipose tissue lipogenic and inflammatory gene expression were found in the gorging mice by metabolic state (fed versus fasted). Additionally, despite a reduced cumulative food intake compared to mice fed ad libitum, restriction-induced gorging mice had increased intraabdominal fat accumulation, diminished hepatic and peripheral insulin sensitivity, and a gene expression profile favoring lipid deposition. Our findings highlight the intraday differences in gene expression in gorging mice before and after feeding that confound comparisons with mice fed ad libitum, or nibbling. The present study also provides evidence that weight regain following food restriction is associated with cumulative metabolic and behavioral abnormalities in mice. Copyright © 2015. Published by Elsevier Inc.The Journal of nutritional biochemistry 03/2015; DOI:10.1016/j.jnutbio.2015.01.010 · 4.59 Impact Factor
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ABSTRACT: Research suggests that sex may condition atherosclerosis development against different genetic backgrounds. This study addresses the hypothesis that this effect would be exerted by changes in the different apolipoproteins present in high-density lipoproteins. ApoE-deficient mice of both sexes with Ola 129 and C57BL/6J genetic backgrounds were fed a chow diet for 14 weeks. At the end of the dietary intervention, the development of atherosclerotic lesions, apolipoproteins, lipid metabolism, inflammation and paraoxonase were assessed. Differences between atherosclerotic lesions in Ola 129 and C57BL/6J strains of apoE-deficient mice were sex-dependent and were only statistically significant in females. Plasma levels of HDL cholesterol and apolipoproteins related to these lipoparticles, such as apoA-I, apoA-II, apoA-IV, apoA-V and apoJ, were significantly different between these two strains and there were sex-related differences in some of these apolipoproteins. Hepatic steatosis was also related to the strain and was independent of sex. In females, changes in HDL cholesterol and apolipoproteins A-I and A-II were important determinants of atherosclerosis, while this was not the case in males. Our results demonstrate that atherosclerosis-related differences between Ola129 and C57BL/6J genetic backgrounds in apoE-deficient mice are sex-dependent and that this finding is explained by the differences in HDL cholesterol and its apolipoprotein components, mainly apoA-I and A-II. Overall, our findings highlight the importance of taking sex into account in the analysis of atherosclerosis and lipid metabolism in animal models.Journal of atherosclerosis and thrombosis 05/2010; 17(7):712-21. DOI:10.5551/jat.3541 · 2.77 Impact Factor