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  • That DGAT mediated hepatic steatosis did

    2021-01-13

    That DGAT-mediated hepatic steatosis did not lead to insulin resistance was clearly demonstrated in Liv-DGAT2-low mice by their normal blood glucose and plasma insulin levels, normal glucose and insulin tolerance, normal insulin sensitivity by hyperinsulinemic-euglycemic clamp studies, and normal hepatic insulin signaling. Because this result was surprising, we analyzed mice expressing high levels of DGAT2 or DGAT1 in the liver. In each instance, hepatic steatosis did not cause glucose intolerance. Thus, hepatic steatosis mediated by DGAT overexpression is insufficient to cause insulin resistance in mice. Since hepatic steatosis and insulin resistance are often associated, other explanations must account for the relationship. One possibility is that hepatic steatosis, when present, is the result of insulin resistance, possibly because the insulin signaling pathways that drive fatty treat biosynthesis in the liver are relatively sensitive to the high levels of insulin that accompany systemic insulin resistance. Alternatively, the two conditions may be separate manifestations of metabolic derangements, and hepatic insulin resistance may reflect inflammation rather than lipid accumulation in this tissue (Arkan et al., 2005). Indeed, although plasma transaminase levels were modestly increased in Liv-DGAT2 mice, the levels of plasma and hepatic inflammatory markers were not increased, consistent with a lack of inflammation. This raises the interesting possibility that increased DGAT activity, by providing a sink for nonesterified lipids, is anti-inflammatory in the liver. Of note, the livers of Liv-DGAT1 and Liv-DGAT2-high mice exhibited apparently increased PERK phosphorylation, consistent with increased ER stress. However, in contrast to what has been reported for murine obesity models (Ozcan et al., 2004), ER stress activation in our models was not associated with insulin resistance. Several recent studies in mice agree with our finding that hepatic steatosis and insulin resistance may be dissociated. Antisense oligonucleotide treatment targeting the gene for DGAT2 reduces liver TG content in mice fed a high-fat diet without improving insulin or glucose tolerance (Yu et al., 2005). Also, prolonged fasting (16 hr) in mice induces hepatic steatosis without causing hepatic insulin resistance (Heijboer et al., 2005). However, insulin resistance is present in other rodent models of primary hepatic steatosis. The expression of lipoprotein lipase in the liver of transgenic mice causes hepatic steatosis and hepatic insulin resistance as manifested by increased hepatic glucose output (Kim et al., 2001). Also, hepatic overexpression of mitochondrial glycerol-3-phosphate acyltransferase in rats is associated with hepatic and peripheral insulin resistance (Nagle et al., 2007). A contrasting intervention, the expression of malonyl-CoA decarboxylase in liver of rats with diet-induced insulin resistance, resolves hepatic steatosis and improves whole-animal, liver, and muscle insulin sensitivities (An et al., 2004). What accounts for the variable relationship between hepatic steatosis and insulin resistance? One possible explanation may be a requirement for an as yet unidentified specific lipid or lipid-derived metabolite that affects insulin sensitivity. Further studies involving the direct comparison of different steatosis models and broader profiling of lipid-derived metabolites may clarify these issues. Hepatic DGAT overexpression had interesting effects on hepatic and plasma TG metabolism. The two DGAT enzymes differed significantly in their ability to generate steatosis in transgenic mice. Relatively small increases in DGAT2 mRNA levels resulted in large increases in hepatic TG content, whereas large increases in DGAT1 mRNA, which in part reflect the low basal levels of DGAT1 expression in mouse liver (Cases et al., 1998), were not accompanied by similarly marked steatosis. These results are consistent with our previous finding that DGAT2 is much more potent and specific than DGAT1 in promoting TG synthesis (Stone et al., 2004, Yen et al., 2005) and with a recent report of overexpression of DGAT enzymes in the liver mediated by adenoviruses (Millar et al., 2006). Additionally, both DGAT1 and DGAT2 overexpression in the liver of transgenic mice increased hepatic TG accumulation but did not increase (and in fact lowered) plasma TG. Because TG secretion was similar in Liv-DGAT2 and WT mice, the lower plasma TG levels most likely reflect alterations in the clearance of TG from the blood. Our findings agree with findings of short-term adenovirus-mediated overexpression of DGAT enzymes in the liver (Millar et al., 2006) and support the hypothesis that factors other than TG synthesis are rate limiting for hepatic TG secretion. However, in another study in mice, longer-term adenovirus-mediated overexpression of DGAT1 resulted in increased hepatic TG secretion (Yamazaki et al., 2005).