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Dysregulated hepatic de novo lipogenesis contributes to the pathogenesis of nonalcoholic fatty liver disease in both humans and rodents. Clinical evidence suggests fatty liver to have a positive correlation with serum lead (Pb2+) levels. However, an exact mechanism of Pb2+‐induced fatty liver progression is still unknown. Here, we show that exposure to Pb2+ regulates ChREBP‐dependent hepatic lipogenesis. Presence of Pb2+ ions within the hepatocytes reduces transcript and protein levels of sorcin, a cytosolic adaptor partner of ChREBP. Adenovirus‐mediated overexpression of sorcin in Pb2+ exposed hepatocytes and an in vivo mouse model ameliorates liver steatosis and hepatotoxicity. Hereby, we present Pb2+ exposure to be a lethal disruptor of lipid metabolism in hepatocytes and highlight sorcin as a novel therapeutic target against Pb2+‐induced hepatic dyslipidemia.
Albumin
is the most abundant serum protein and shows variation
in its synthesis rate in different physiological and pathophysiological
conditions. Thus, there might be an association expected between serum
albumin concentration and body health. A library of NIR probes engineered
with the optimum hydrophobicity has been developed and characterized
using spectroscopy techniques and was employed to understand the variation
of hepatic albumin synthesis rates on physiological and pathophysiological
states. Given the importance of hydrophobicity in rendering an effective
interaction of small molecules with biomolecules, strategic structure
interaction relationship studies led us toward the development of
a potent emissive molecular probe through chemical library development.
By exploration of these newly developed molecular probes, our study
elegantly showed how a pathophysiological condition like the hyperinsulinemic
state significantly downregulates albumin biosynthesis in HepG2 cells
using fluorescence microscopy as a tool. An excellent correlation
between the albumin transcript level and fluorescence intensity inside
the cells has been observed. The key role of hydrophobicity resulting
in an effective interaction of the probes with albumin, thus leading
to strong optical signals, has been experimentally demonstrated in
this report. Also, a siRNA interference technique has been utilized
to establish the excellent selectivity of the developed probes with
excitation as well as emission in the NIR region. We therefore have
established through our experimental findings that suitable cell permeable
emissive molecular markers with a high degree of albumin specificity
can be used as a good optical tool for studying the effect of hyperinsulinemia
on albumin biosynthesis modulation.
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