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Page 8 of 18 Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90

Transmembrane-6 superfamily-2 (TM6SF2) is another gene that regulates lipid metabolism and has been
implicated on the pathogenesis of NAFLD. TM6SF2 modulates intestinal cholesterol absorption and
clearance, hepatic cholesterol biosynthesis and secretion, as well as the flux of triglycerides from lipid
droplets to the synthesis and secretion of very low-density lipoproteins (VLDL) from the liver [40,120] . A
variant of TM6SF2, rs58542926 C>T, possesses a substitution of glutamate for lysine at position 167 (E167K),
and is a loss-of-function variant that increases the risk of NAFLD and hepatocellular carcinoma, albeit
decreasing circulating lipids and protecting from cardiovascular disease [121-125] .

Regarding the association between TM6SF2 rs58542926 and lean-NAFLD, two studies found a higher
prevalence of the T allele in lean compared to overweight/obese patients with NAFLD [118,126] . However,
others could not reproduce those findings [28,117] .

Cholesteryl ester transfer protein mediates the exchange of triglycerides from triglycerides-rich lipoproteins
to HDL, allowing reverse cholesterol transport from peripheral tissues back to the liver. Two variants,
rs12447924 and rs12597002, are associated with NAFLD in lean individuals, but not obese individuals, in
an Australian cohort [127] .

SREBP-2 regulates cholesterol biosynthesis, uptake, and excretion. The SREBP-2 polymorphism rs133291
is associated with increased risk of NAFLD and steatohepatitis in non-obese, non-diabetic patients without
the MS, once again helping to explain a dissociation between NAFLD and metabolic disturbances and
obesity [128] .

Lastly, a variant in phosphatidylethenolamine N-methyltransferase (PEMT), rs7946 C>T was associated
with lean-NAFLD and unhealthy lipid profile with an increase in low-density lipoproteins (LDL) and
a decrease in HDL [129,130] . PEMT catalyzes de novo synthesis of choline, which is required for the export
of hepatic triglycerides as VLDL [131] . Accordingly, patients with lean-NAFLD have low hepatic PEMT
expression [132] .

It would be interesting to evaluate whether lean patients with NAFLD have an increased risk of carrying at
least one of the above different risk alleles as compared to overweight/obese NAFLD.

Microbiota
Microbiota may have a strong role on the development of NAFLD in lean subjects. When comparing
the microbiota from lean and overweight/obese patients, significant differences have been consistently
reported [43,126,133] .

A multicenter study recruited patients from Italy and Australia, and found that lean-NAFLD, compared
to non-lean NAFLD and controls, had an altered fecal microbiota profile. Lean patients had enrichment
of the genera Erysipelotrichaceae UCG-003, Ruminococcus, Clostridium sensu stricto 1, Romboutsia, and
Ruminococcaceae UCG-008, and an impoverishment of Ruminiclostridium and Streptococcus, as compared
to non-lean patients [126] . This microbiota profile of lean patients seems to promote the formation of
bile acids, and hence to associate with increased levels of secondary bile-acids, as well as FGF-19. This
increase in bile acids and FGF-19 could explain a metabolic adaptation to an obesogenic diet, promoting
a peripheral increase in energy expenditure. On the other hand, as compared to healthy subjects, lean-
NAFLD patients showed impoverishment of species believed to be protective against hepatic steatosis such
as Marvinbryantia and Christensellenaceae R7 group, and enrichment of Dorea species that have previously
been associated with NASH [126] .

Other studies found impoverishment of potentially protective bacteria such as Faecalibacterium and
[43]
Lactobacillus . Faecalibacterium prausnitzii are butyrate-producing bacteria with known immune-