Page 66 - ITPS-7-4

INNOSC Theranostics and
Pharmacological Sciences Role of saroglitazar in MASH

1. Introduction is essential for the development of multiple sclerosis
lipogenesis (MASLD) by increasing the liver’s ability to
Metabolic dysfunction-associated steatohepatitis (MASH) use free fatty acids, which in turn causes fatty liver and
is a metabolic disease marked by hepatic fat buildup and lipotoxicity. 5,6
significant inflammation. From metabolic dysfunction-
associated fatty liver to MASH, metabolic dysfunction- The American Association for the Study of Liver
associated steatotic liver disease (MASLD) encompasses a Diseases recommendations emphasize that only biopsy-
1
7,8
wide range of chronic liver diseases. Significant data has confirmed MASH warrants medical intervention
surfaced in the last 20 years demonstrating the worldwide While various medications have been explored for
occurrence of MASLD and linking it to a range of liver MASH treatment, none have received official approval.
7
conditions, including those that can lead to cirrhosis and Among the medications considered are glitazones, with
hepatocellular carcinoma. Most of the cases with MAFLD pioglitazone being one example. Studies have shown that
are asymptomatic and are diagnosed incidentally. 2 pioglitazone can improve NAFLD activity score, lead
to MASH resolution, and enhance fibrosis, along with
A severe type of MASLD that affects 35 million
individuals worldwide, MASH is linked to hepatocellular improving histological aspects like steatosis, inflammation,
9,10
inflammation as a result of fat buildup in the cells. MASLD and hepatocellular ballooning.
significantly adds to the worldwide burden of illness. The In MASLD, the primary goal of pharmacological
prevalence of MASLD is 25.24% worldwide, with South intervention is to manage liver inflammation and fibrosis.
America and the Middle East having the highest rates. In This is due to the fact that in individuals with MASLD, the
India, the prevalence of adult MASLD has been reported degree of liver inflammation and fibrosis is strongly linked
between 6.7% and 55.1%, whereas that of pediatric MASLD to both extrahepatic and hepatic morbidity and mortality.
has been reported between 7.3% and 22.4%. Obesity, A dual proliferator peroxisome activated receptor
type 2 diabetes, dyslipidemia, hypertension, and metabolic (PPAR)-α/γ agonist called saroglitazar magnesium was
syndrome are the common metabolic comorbidities linked created to lessen the negative effects of selective PPAR-γ
to MASLD. It has been estimated that 33.5% of adults agonism. For saroglitazar, the proposed mechanism of
worldwide will be affected by MASLD and another 27% action involves targeting PPAR-α and PPAR-γ, which
will have MASH by 2030. leads to an enhancement in insulin sensitivity and lipid
MASLD-related hepatocyte steatosis is typified by the oxidation. This dual mechanism reduces lipotoxicity by
accumulation of fat droplets in the hepatocytes. MASH decreasing fat accumulation in the liver and improving fat
may occur from hepatocellular damage and inflammation, metabolism there. 11,12 It inhibits the production and release
either in conjunction with or apart from hepatic fibrosis. of triglycerides (TG), increases the hepatic oxidation of
Factors including insulin resistance, oxidative stress, fatty acids, and through PPAR-α agonism, improves the
inflammation, altered adipokine and cytokine secretion, levels of lipoproteins in circulation. Furthermore, through
altered lipid metabolism, and endoplasmic reticulum stress PPAR-γ agonism, saroglitazar decreases blood glucose and
are associated with these disorders. These characteristics glycosylated hemoglobin (HbA1c) levels, enhances insulin
make MASH a clinically aggressive form of MASLD, sensitivity, and controls the transcription of genes that
and individuals with MASH are more likely to develop respond to insulin. In India, saroglitazar has been licensed
cirrhosis. As a result, for the past several years, attempts for the treatment of hypertriglyceridemia and diabetic
have been made to study and develop drugs specifically for dyslipidemia since 2013. In addition, it has been authorized
this condition. in some other countries, to treat hypertriglyceridemia and
dyslipidemia in type 2 diabetic patients whose condition is
The primary diagnostic subtype of MASLD is not managed by statins.
MASH, which carries a risk of cirrhosis and liver-
related consequences. However, it is important to note Numerous investigations, including human and animal
that all subtypes of MASLD elevate the likelihood of MASLD models, have demonstrated its effectiveness in
cardiovascular events and mortality. Projections suggest a reducing hepatic steatosis, hepatocellular inflammation,
steep increase in the prevalence of MASLD patients in the and fibrogenic activity. 13,14 Saroglitazar has been shown
coming years, driven by the growing rates of obesity and in animal models to decrease alanine aminotransaminase
type 2 diabetes. MASLD often emerges in individuals (ALT) levels and to alleviate hepatic steatosis, hepatocellular
3,4
with a medical history of diabetes and obesity. Our ballooning, and lobular inflammation in MASH caused
understanding of MASLD’s etiology and progression has by a high-fat, choline-deficient diet or Western diet.
significantly expanded in recent decades. The well-known Moreover, saroglitazar was shown to significantly lower
“multiple hit hypothesis” suggests that insulin resistance insulin resistance, TG, total cholesterol, and metabolically

Volume 7 Issue 4 (2024) 2 doi: 10.36922/itps.3560