Avasimibe and Sirt 1 Activators Reverse NAFLD and Obesity-Juniper Publishers
Novel Approaches in Drug Designing & Development (NAPDD)
In epidemiological studies human obesity is clearly
associated with the increased risk for atherosclerosis contributing to
the early onset of coronary artery disease and diabetes. Visceral
obesity in particular increases the risk of atherosclerosis owing to
both insulin resistance and dyslipoproteinemia. Risk factors for
atherosclerosis that could be exacerbated by obesity include
hypertension and hyper lipidemia particularly hyper triglyceridemia
which are risk factors for Alzheimer’s disease. The susceptibility of
humans to obesity is far higher compared with other species and in man
favours the deposition of fat [1]. Amongst mammals humans have been
reported to have the highest level of fatness than any other species and
genes and environmental factors predispose humans to obesity [2]. Novel
research provides information for anti-aging genes with connections
between appetite dysregulation, circadian desynchrony and non alcoholic
fatty liver disease (NAFLD) in obesity [3]. Sirtuins are NAD+dependent
protein de acetylates that target transcription factors to adapt gene
expression to metabolic activity. Sirtuin 1 (Sirt1) is linked to life
span, obesity and cardiovascular disease with effects on liver
steatosis, inflammation, food intake, energy metabolism, cognition,
mitochondrial biogenesis, neurogenesis, glucose/cholesterol metabolism
and amyloidosis [3,4]. Regulation by calorie restriction of Sirt1 in
extending life span has been recognized with novel dietary activators of
Sirt1required [3] that have therapeutic potential for reversal of high
fat induced metabolic damage with the prevention of NAFLD [5,6].
The understanding of molecular mechanisms that
predispose individuals to obesity may involve high fat diets involved in
Sirt 1 repression linked to the defective adipose tissue-liver
crosstalk [7-9]. Molecular mechanisms involving diet and drugs that
target and reduce the size of the adipose tissue and the development of
obesity have become of interest to the biomedical community. The enzyme
acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) esterifies
cholesterol with long-chain fatty acids, and thereby controls the
absorption of cholesterol and dietary fat from the intestine [10] that
plays an important role in hepatic apo B (cholesterol lipoproteins) and
amyloid beta generation [11-14]. The use of ACAT inhibitors such as
Avasimibe [15,16] reduce intestinal fatand regulate adipose tissue size
to maintain liver ACAT activity and hepatic apo B metabolism [11].
In high fat studies in mice after 6 week mice
developed liver steatosis with neuro degeneration [16]. The ACAT
inhibitor Avasimibe in mice reduced intestinal fat absorption and
reversed fatty liver and neuro inflammation with marked improvement in
growth when compared with mice not consuming Avasimibe. An ACAT
inhibitor such as Avasimibe (Figure 1) may provide better therapy to
maintain the hepatic and brain Sirt1 activity and halt and delay the
onset of liver and brain oxidative stress in obesity and other chronic
diseases [3]. Avasimibe can be considered as an anti-aging drug that
targets the periphery (adipose tissue-liver crosstalk) [7,8] and the
brain with relevance to its use with other synthetic Sirt 1activating
compounds [17] that require evaluation and assessment in rodent, primate
and human trials.
Conclusion
Healthy diets and its therapeutic use in obesity and diabetes
may be ineffective with relevance to drug induced mitophagy
[18]. Avasimibe and its use with other Sirt 1 activators have
become of importance to drug therapy in obesity and diabetes
with relevance to the acceleration of hepatic drug metabolism
with the prevention of mitochondrial apoptosis [18]. The use
of synthetic Sirt 1 activators with healthy diets may prevent
brain disease (Figure 1) and NAFLD that are associated with the
induction of global obesity linked diabetes [19].
Acknowledgement
This work was supported by grants from Edith Cowan
University, the McCusker Alzheimer’s Research Foundation and
the National Health and Medical Research Council.
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