Sandbox Reserved 1769: Difference between revisions

Line 36:

Bile salts are derived from [https://en.wikipedia.org/wiki/Cholesterol cholesterol], and they serve an important role in the mechanical digestion of fats and ultimately facilitate the chemical digestion of lipids.<Ref name="Patton"> Patton JS, Carey MC. Watching fat digestion. Science. 1979 Apr 13;204(4389):145-8. [https://dx.doi.org/10.1126/science.432636 DOI: 10.1126/science.432636]. </Ref> Their [https://en.wikipedia.org/wiki/Amphiphile amphipathicity] allows them to solubilize hydrophobic fats for transport in aqueous bodily fluids.<ref name = "Patton" /> Without bile salts, fats would spontaneously separate out of the aqueous solution in the duodenum and would not be accessible to [https://en.wikipedia.org/wiki/Pancreatic_lipase_family#Human_pancreatic_lipase pancreatic lipase] for breakdown. Proper fat digestion requires both pancreatic lipase and bile; thus, NTCP's function in recycling bile salts is critical.<ref name = "Patton" /> Additionally, bile acids play a major role in the regulation of lipid and energy metabolism. In mice, targeting NTCP-mediated bile acid was shown to treat obesity and obesity-related [http://www.example.com hepatosteatosis] through the simultaneous dampening of intestinal fat absorption and increasing energy expenditure.<Ref name="Donkers"> Donkers JM, Kooijman S, Slijepcevic D, Kunst RF, Roscam Abbing RL, Haazen L, de Waart DR, Levels JH, Schoonjans K, Rensen PC, Oude Elferink RP, van de Graaf SF. NTCP deficiency in mice protects against obesity and hepatosteatosis. JCI Insight. 2019 Jun 25;5(14):e127197. [https://dx.doi.org/10.1172/jci.insight.127197 DOI: 10.1172/jci.insight.127197]. </Ref>

Insight into NTCP's structure and function has implications for therapeutic treatment of HBV/HDV infection. For example, the inhibitory effect of therapeutic antibody Nb87 on myr-preS1 binding shows potential for therapeutics that stabilize NTCP inward facing state as [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] of viral cell entry. <Ref name="Zhang" /> ~~Myrcludex~~ B ~~acts as an inhibitor of HDV~~ infection, ~~yet it suffers~~ the ~~drawback of simultaneously preventing bile salt uptake~~.<ref name="~~Park~~"/>

Insight into NTCP's structure and function has implications for therapeutic treatment of HBV/HDV infection. For example, the inhibitory effect of therapeutic antibody Nb87 on myr-preS1 binding shows potential for therapeutics that stabilize NTCP inward facing state as [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] of viral cell entry. <Ref name="Zhang" /> There have been various studies attempting to identify molecules that inhibit HBV/HDV binding of NTCP while maintaining NTCP's transporter activity. One study has identified a [https://en.wikipedia.org/wiki/Ciclosporin ciclosporin] derivative that has the capability to prevent HBV binding while still allowing NTCP to transport bile salts. <Ref name="Shimura"> Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, Iwamoto M, Tsukuda S, Takeuchi JS, Miyake T, Sugiyama M, Ogasawara Y, Park SY, Tanaka Y, Kusuhara H, Mizokami M, Sureau C, Wakita T. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol. 2017 Apr;66(4):685-692. doi: 10.1016/j.jhep.2016.11.009. [https://dx.doi.org/10.1016/j.jhep.2016.11.009 DOI: 10.1016/j.jhep.2016.11.009]. </Ref> This small molecule is the first to successfully prevent infection against multiple HBV genotypes without hindering normal NTCP activity, highlighting the fact that anti-HBV activity can remain separate from NTCP function.<ref name="Shimura"/> Future studies will work to identify more effective and safe ways to prevent infection without harming normal NTCP function.

Sandbox Reserved 1769: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

Revision as of 18:06, 10 April 2023 view source Margaret Samm (talk \| contribs) 208 edits No edit summary ← Older edit		Revision as of 18:13, 10 April 2023 view source Benjamin Minor (talk \| contribs) 80 edits No edit summary Newer edit →
Line 36:		Line 36:
	Bile salts are derived from [https://en.wikipedia.org/wiki/Cholesterol cholesterol], and they serve an important role in the mechanical digestion of fats and ultimately facilitate the chemical digestion of lipids.<Ref name="Patton"> Patton JS, Carey MC. Watching fat digestion. Science. 1979 Apr 13;204(4389):145-8. [https://dx.doi.org/10.1126/science.432636 DOI: 10.1126/science.432636]. </Ref> Their [https://en.wikipedia.org/wiki/Amphiphile amphipathicity] allows them to solubilize hydrophobic fats for transport in aqueous bodily fluids.<ref name = "Patton" /> Without bile salts, fats would spontaneously separate out of the aqueous solution in the duodenum and would not be accessible to [https://en.wikipedia.org/wiki/Pancreatic_lipase_family#Human_pancreatic_lipase pancreatic lipase] for breakdown. Proper fat digestion requires both pancreatic lipase and bile; thus, NTCP's function in recycling bile salts is critical.<ref name = "Patton" /> Additionally, bile acids play a major role in the regulation of lipid and energy metabolism. In mice, targeting NTCP-mediated bile acid was shown to treat obesity and obesity-related [http://www.example.com hepatosteatosis] through the simultaneous dampening of intestinal fat absorption and increasing energy expenditure.<Ref name="Donkers"> Donkers JM, Kooijman S, Slijepcevic D, Kunst RF, Roscam Abbing RL, Haazen L, de Waart DR, Levels JH, Schoonjans K, Rensen PC, Oude Elferink RP, van de Graaf SF. NTCP deficiency in mice protects against obesity and hepatosteatosis. JCI Insight. 2019 Jun 25;5(14):e127197. [https://dx.doi.org/10.1172/jci.insight.127197 DOI: 10.1172/jci.insight.127197]. </Ref>		Bile salts are derived from [https://en.wikipedia.org/wiki/Cholesterol cholesterol], and they serve an important role in the mechanical digestion of fats and ultimately facilitate the chemical digestion of lipids.<Ref name="Patton"> Patton JS, Carey MC. Watching fat digestion. Science. 1979 Apr 13;204(4389):145-8. [https://dx.doi.org/10.1126/science.432636 DOI: 10.1126/science.432636]. </Ref> Their [https://en.wikipedia.org/wiki/Amphiphile amphipathicity] allows them to solubilize hydrophobic fats for transport in aqueous bodily fluids.<ref name = "Patton" /> Without bile salts, fats would spontaneously separate out of the aqueous solution in the duodenum and would not be accessible to [https://en.wikipedia.org/wiki/Pancreatic_lipase_family#Human_pancreatic_lipase pancreatic lipase] for breakdown. Proper fat digestion requires both pancreatic lipase and bile; thus, NTCP's function in recycling bile salts is critical.<ref name = "Patton" /> Additionally, bile acids play a major role in the regulation of lipid and energy metabolism. In mice, targeting NTCP-mediated bile acid was shown to treat obesity and obesity-related [http://www.example.com hepatosteatosis] through the simultaneous dampening of intestinal fat absorption and increasing energy expenditure.<Ref name="Donkers"> Donkers JM, Kooijman S, Slijepcevic D, Kunst RF, Roscam Abbing RL, Haazen L, de Waart DR, Levels JH, Schoonjans K, Rensen PC, Oude Elferink RP, van de Graaf SF. NTCP deficiency in mice protects against obesity and hepatosteatosis. JCI Insight. 2019 Jun 25;5(14):e127197. [https://dx.doi.org/10.1172/jci.insight.127197 DOI: 10.1172/jci.insight.127197]. </Ref>

	Insight into NTCP's structure and function has implications for therapeutic treatment of HBV/HDV infection. For example, the inhibitory effect of therapeutic antibody Nb87 on myr-preS1 binding shows potential for therapeutics that stabilize NTCP inward facing state as [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] of viral cell entry. <Ref name="Zhang" /> ~~Myrcludex~~ B ~~acts as an inhibitor of HDV~~ infection, ~~yet it suffers~~ the ~~drawback of simultaneously preventing bile salt uptake~~.<ref name="~~Park~~"/>		Insight into NTCP's structure and function has implications for therapeutic treatment of HBV/HDV infection. For example, the inhibitory effect of therapeutic antibody Nb87 on myr-preS1 binding shows potential for therapeutics that stabilize NTCP inward facing state as [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] of viral cell entry. <Ref name="Zhang" /> There have been various studies attempting to identify molecules that inhibit HBV/HDV binding of NTCP while maintaining NTCP's transporter activity. One study has identified a [https://en.wikipedia.org/wiki/Ciclosporin ciclosporin] derivative that has the capability to prevent HBV binding while still allowing NTCP to transport bile salts. <Ref name="Shimura"> Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, Iwamoto M, Tsukuda S, Takeuchi JS, Miyake T, Sugiyama M, Ogasawara Y, Park SY, Tanaka Y, Kusuhara H, Mizokami M, Sureau C, Wakita T. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol. 2017 Apr;66(4):685-692. doi: 10.1016/j.jhep.2016.11.009. [https://dx.doi.org/10.1016/j.jhep.2016.11.009 DOI: 10.1016/j.jhep.2016.11.009]. </Ref> This small molecule is the first to successfully prevent infection against multiple HBV genotypes without hindering normal NTCP activity, highlighting the fact that anti-HBV activity can remain separate from NTCP function.<ref name="Shimura"/> Future studies will work to identify more effective and safe ways to prevent infection without harming normal NTCP function.