2.2. SREBP1-
In the livers of HFHS mice, ob/ob mice, db/db mice, and also the
individuals with NAFLD, FOXO3 expressions were elevated. In HepG2 cells,
FOXO3 overexpression enhanced cellular TG concentrations while FOXO3
knockdown decreased them. In C57BL/6 J mice on a chow diet,
gain-of-function of FOXO3 led to the deposition of hepatic TG, also when
a high-fat diet is given, it exacerbated hepatic steatosis. The enhanced
expression of TG synthesis-related genes such as SREBP1c, in the liver
of mice, was determined by transcript analysis. In a mechanism-based
manner, FOXO3 knockdown decreased SREBP1c expression while FOXO3
overexpression increased it. SREBP1c modulated the transcription of the
SREBP1c promoter, according to luciferase reporter tests. By encouraging
the SREBP1c promoter’s transcriptional activity, FOXO3 increases TG
formation along with its hepatic accumulation (Wang et al., 2019). There
is proof that diets high in saturated fat, like those high in palmitate,
stimulate the development of Aβ, the histological sign of AD. The
mechanisms underlying the harmful consequences of a diet high in
palmitate on the stimulation of Aβ genesis have not yet been fully
understood. The gene expressions which code for the protein intricated
in nearly every aspect of lipid metabolism are regulated by the
transcription factor sterol response element binding protein 1 (SREBP1),
which is altered by saturated fatty acids like palmitate. The study
established how alterations in SREBP1 expression as well as in
transcription contributed to the impacts that palmitate had on Aβ
genesis along with on Beta-secretase 1(BACE1) expression. This research
identifies SREBP1 activation as a unique molecular factor in the
upregulation of BACE1 expression brought on by palmitate and subsequent
Aβ generation. However, the role of SREBP1 in AD linked with liver
disorder is not well understood on the molecular level. But up to the
present work, no molecular research had yet suggested that SREBP1
dysregulation was responsible for the regulation of AD-related processes
(Marwarha et al., 2019). Age-related disorders including AD and glucose
and lipid homeostasis have both been linked to FOXOs. Significant
metabolic abnormalities in the brain are also present in AD.
Misregulation of the FOXO signaling pathway may be the cause of
age-related functional decline and age-related illnesses due to its
important involvement in metabolic balance and organismal lifespan (Du
et al., 2021). However, FOXO has a significant role in the development
of liver diseases like NAFLD, which is not well understood. In the
above-concluded studies, the experiments were designed to examine the
effects of FOXO modulation in liver-associated AD. Thus, it can be said
that FOXO has a beneficial role in protecting the fatty liver disease
induced by diet (Pan et al., 2017). Whereas, this expression of
inflammation might lead to the development of AD and FOXO might play a
protective role in it. However, no molecular studies have been
implicated yet.