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Gene & Protein in Disease Hydrogen sulfide ameliorates NAFLD

namely steatosis, non-alcoholic steatohepatitis (NASH), reduce blood lipids, and offer antioxidant properties.
hepatic fibrosis (HF), and cirrhosis (HC). NAFLD Given the current state of knowledge, it remains crucial
2,3
conventionally encompasses both steatosis and NASH, to continue delving into the mechanisms behind NAFLD
where steatosis is diagnosed when liver fat content exceeds onset and alleviation through comprehensive experimental
5% of liver weight, and NASH is characterized by substantial studies and to advance and validate promising new drug
fat deposition, inflammatory cell infiltration, liver swelling, candidates for this condition. 16
and hepatocyte ballooning. The stages of NAFLD, Hydrogen sulfide (H S), known for its noxious
4
including NASH, HF, and HC, often result in significant smell resembling rotten eggs, is considered a toxic gas.
2
liver damage and are commonly seen as progressive stages. However, over the past two decades, extensive research
NAFLD can lead to potentially fatal hepatic failure, has established H S as a significant biological signaling
5,6
with a high mortality rate, as well as an increased risk of molecule, ranking as the third gaseous signaling molecule
2
hepatocellular carcinoma (HCC) compared to the general after nitric oxide and carbon monoxide. 17-20 In mammals,
population. Clinical statistics indicate that around 30% of H S can be generated through two different pathways:
7,8
2
patients with steatosis will progress to NASH. During the enzyme-catalyzed and non-enzyme-catalyzed. There
repair process following NASH-induced liver injury, scar are four known enzyme-catalyzed pathways for H S
tissue formed by hepatic stellate cells gradually replaces the production in mammals: the cystathionine β-synthase
2
damaged liver tissue, leading to fibrosis within the hepatic pathway, the cystathionine γ-lyase pathway, the cysteine
sinusoids or localized areas. As liver fibrosis progresses, it aminotransferase-mercaptopyruvate sulfur transferase
gradually distorts the liver’s normal histological structure (MPST) pathway, and the D-amino acid oxidase-MPST
through processes such as cell death, nodular regeneration, pathway. 21-24 Once synthesized, H S can freely diffuse
2
connective tissue proliferation, and fibrosis, eventually across the cell membranes and exists within cells in
25
leading to cirrhosis. Cirrhosis usually results in multiple- three distinct forms: free sulfur, bound thioalkyl sulfur,
system damage and may lead to complications such as and acid-unstable sulfur. These three forms represent the
upper gastrointestinal bleeding, hepatic encephalopathy, major storage pools of H S. Under physiological pH
26
2
9,10
and secondary infections in the advanced stages. In conditions, free sulfur includes H S molecules (~20%),
addition, NAFLD patients have a higher risk of developing HS , and a minor amount of S . Thioalkyl sulfur refers
2
2-
-
HCC, with NAFLD-related HCC cases accounting for to sulfur atoms bound to other kinds of sulfur, such as
approximately 25% of all liver cancer cases. 11 the external sulfur atoms of persulfides and the internal
27
At present, the pathogenesis of NAFLD is most sulfur atoms of polysulfides. Bound thioalkyl sulfur
commonly explained by the “two-hit” theory and its includes various forms, including persulfate, thiosulfate
subsequent development, the “multiple parallel hits” (S O ), polysulfide, polysulfate, and sulfur bound to
2-
3
2
theory. These theories offer a comprehensive framework proteins. Acid-unstable sulfur, a common feature in living
12
for understanding how NAFLD is interconnected with organisms, primarily comprises iron-sulfur clusters, which
obesity, type 2 diabetes, and dyslipidemia, as well as serve as a major H S storage reservoir in humans and mice,
2
how these conditions contribute to the advancement with hemoglobin being an exception. The transformation
of NAFLD. Insulin resistance and oxidative stress are of H S into its different forms is highly dynamic. 28
2
13
regarded as pivotal factors in the development of NAFLD. A wealth of recent research has demonstrated the
The “multiple parallel hits” theory aligns with the “two- involvement of H S in the regulation of numerous
hit” theory at the cellular level, while also incorporating physiological and pathological processes in mammals. 29-33
2
14
genetic factors, lifestyle influences, and interactions among For instance, administration of the H S donor sodium
2
the liver, adipose tissue, pancreatic tissue, and the intestinal hydrosulfide (NaHS) has been shown to effectively reduce
environment. This theory posits that these multifaceted fibrosis in a rat model of kidney injury by attenuating
factors intertwine and collectively promote the onset and tissue oxidative stress and inflammation. Similarly, the
34
progression of NAFLD. 15 H S donor GYY4137 has shown remarkable efficacy in
2
Despite the vast potential and competitive nature of mitigating damage from myocardial ischemia-reperfusion
the NAFLD drug market, with multiple drugs currently in rats by inhibiting cellular oxidative stress and apoptosis.
35
in clinical trials, no targeted drug has yet been approved In addition, compelling research data indicate a notable
for market release. Existing treatment options for NAFLD correlation between H S levels and NAFLD. The current
2
primarily involve a range of lifestyle interventions based study revealed a significant association between H S levels
2
on mechanistic research, as well as the repurposing of and NAFLD, demonstrating its potential in alleviating
established medications that enhance insulin sensitivity, NAFLD symptoms in mice. Subsequent investigations
Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.3409