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Page 6 of 10 Chidambaranathan-Reghupaty et al. Hepatoma Res 2018;4:32 I http://dx.doi.org/10.20517/2394-5079.2018.34

tunicamycin or ectopic expression of activating transcription factor 6 (ATF6), a crucial transcription factor
in the unfolded protein response triggered by ER stress. Simulating ER stress in human liver cancer results
[50]
in an increase in SND1 promoter activity showing that SND1 has a role in ER stress response . However,
the functional consequence of this observation is yet to be elucidated. In response to DNA damage, SND1
[51]
is recruited to the damage site by Poly ADP-ribose polymerase 1 (PARP-1), a DNA damage sensor . The
accumulated SND1 recruits to the damage site ATP-dependent chromatin remodeler (ARCA5) and histone
acetyltransferase (GCN5), two enzymes that promote chromatin relaxation to enable access of DNA damage
response related proteins to the damage site. This results in chromatin relaxation and consequent activation
of ATM kinase and downstream DNA repair signaling pathways. Thus SND1 functions as a key determinant
providing survival advantage under DNA damage stress.

ROLE OF SND1 IN LIPID METABOLISM
One of the most important metabolic alterations that occur during tumor development is the deregulation
of lipid metabolism. Specifically, lipid biosynthesis rate is increased to provide a survival advantage for
tumors. Lipids act as signaling molecules, disrupt normal tissue architecture, promote tumor migration
[52]
and induce angiogenesis . Increased lipid synthesis causes steatogenesis or lipid accumulation, a common
feature in carcinomas. In HCC, it is reflected by the formation of cytosolic organelles called lipid droplets
[53]
(LDs) comprised of a core of neutral lipids coated by amphipathic lipids and associated proteins . The
role of SND1 in lipid metabolism was evidenced when it was found on the surface of LDs originating from
[54]
the ER in mammary epithelial cells and adipocytes . SND1 interacts with a lipoprotein part of the fatty
acid synthase (FASN) complex to form LDs. Under steatogenic conditions, SND1 is targeted from cell
[55]
compartments like the ER and golgi complex to low density LDs to facilitate their assembly .
In addition to lipid storage, SND1 is involved in lipid transport. Once fatty acids are taken up from dietary
sources or synthesized in the liver, they are transported to other locations in the body to serve energy
demands. Hepatocytes use lipoproteins made up of a non-polar lipid core surrounded by apolipoproteins
and amphipathic lipids like phospholipids and cholesterol for this purpose. Though they are structurally
similar to LDs, their main function is lipid transport rather than storage. Overexpression of SND1 promotes
the secretion of phospholipids that form a part of the lipoproteins in primary hepatocytes and facilitates the
[56]
transfer of these phospholipids to apolipoproteins before their secretion from hepatocytes . Cholesterol
is another component of the lipid core in both LDs and lipoproteins, the synthesis of which is regulated by
SND1. Under conditions of cholesterol depletion, SREBP2, a regulator of cholesterol uptake and synthesis
[16]
activates SND1 . Overexpression of SND1 results in increased cholesterogenesis, metabolically coupled to
[57]
cholesterol esterification, causing an increase in cholesteryl ester levels .
Glycerolipids are lipids composed of mono, di- or tri- substituted glycerol moieties that are important
constituents of biological membranes. Rapid synthesis of lipids is required for generation of biological
membranes and facilitating cancer cell proliferation. SND1 induction with TNFα and subsequent
profiling of SND1 promoter activity revealed that SND1 regulates a group of glycerolipid metabolic genes
including CHPT1, LPGAT1, PTDSS1 and LPIN1 that are involved in biosynthesis of phophatidylcholine,
[58]
phosphatidylglycerol, phosphatidylserine and triacylglycerol respectively . SND1 interacts with and inhibits
[41]
monoglycerolipid lipase (MGLL) , a tumor suppressor that converts monoglycerolipids to glycerols and
free fatty acids. Thus, SND1 causes an increase in glycerolipid levels in cells by causing an increase in their
synthesis or preventing their catabolism in hepatocytes [Figure 3].

CONCLUSION
HCC is unique in having defined etiologies, all of which cause chronic inflammation. In addition, altered
lipid metabolism in obesity-associated NASH is becoming a major driving force for HCC. It is intriguing