Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease

Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum

“…Similarly, it is still not known whether the HSD17B13 gene locus influences susceptibility to T2D and insulin resistance. A study by Luukkonen et al have recently reported that in European nondiabetic individuals, the HSD17B13 rs72613567:TA was not significantly associated with changes in fasting glucose and insulin levels or insulin sensitivity, as directly quantified by euglycaemic hyperinsulinaemic clamp technique 123 …”

Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease

“…Furthermore, the rs72613567 variant has been related to a reduced risk of elevated transaminases and HCC in 111, 612 individuals from the Danish general population and in 3, 315 European patients, respectively [135,136]. The likely mechanism behind these genetic associations seems to be due to an increased concentration of phospholipids in the liver of carriers compared to noncarriers, that is coupled to a down-regulation of pro-inflammatory genes [137].…”

A closer look at the mysterious HSD17B13

“…knockout does not seem to protect liver from ALD or NASH (3,17). (6,8,13). More studies are needed to demonstrate whether those changes in phospholipids are consequences of HSD17B13 loss of function on the lipid droplets and whether the enrichment of PC and PE is a major player in the protection from chronic liver disease due to the HSD17B13 deficiency.…”

“…Interestingly, a few single-nucleotide polymorphisms (rs72613567, rs62305723, rs6834314, rs9992651, rs13118664, and rs4607179) of the human HSD17B13 gene have been linked to alcoholic and non-alcoholic fatty liver diseases by genome-wide association studies (5)(6)(7)(8)(9)(10)(11)(12). Loss-of-function mutations in the human HSD17B13 gene due to improper splicing, insertion, or nonsynonymous mutations confer a strong protective effect on liver injury, inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). However, the biochemical structure and function of human HSD17B13 protein remains elusive.…”

“…As the protein structure for human HSD17B13 has not been solved, Ma et al used The second question is why human and mouse HSD17B13 function differently even they are structurally similar at the amino acid sequences with 69% identity and 75% similarity and all the key residues required for dimerization, substrate binding, and catalysis are conserved (according to amino acid sequence alignments). Even though human genetic data strongly suggest HSD17B13 lost-of-function mutations have a protective effect against multiple chronic liver diseases including alcoholic and non-alcoholic fatty liver diseases (5)(6)(7)(8)(9)(10)(11)(12)(13), mouse Hsd17b13 gene by guest, on November 5, 2020…”