Pharmacological SERCA activation limits diet-induced steatohepatitis and restores liver metabolic function in mice

Abstract

Metabolic dysfunction-associated steatotic liver disease is the most common form of liver disease and poses significant health risks to patients who progress to metabolic dysfunction-associated steatohepatitis. Fatty acid overload alters endoplasmic reticulum (ER) calcium stores and induces mitochondrial oxidative stress in hepatocytes, leading to hepatocellular inflammation and apoptosis. Obese mice have impaired liver sarco/ER Ca²⁺-ATPase (SERCA) function, which normally maintains intracellular calcium homeostasis by transporting Ca²⁺ ions from the cytoplasm to the ER. We hypothesized that restoration of SERCA activity would improve diet-induced steatohepatitis in mice by limiting ER stress and mitochondrial dysfunction. WT and melanocortin-4 receptor KO (Mc4r^-/-) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were administered CDN1163 to activate SERCA, which reduced liver fibrosis and inflammation. SERCA activation also restored glucose tolerance and insulin sensitivity, improved histological markers of metabolic dysfunction-associated steatohepatitis, increased expression of antioxidant enzymes, and decreased expression of oxidative stress and ER stress genes. CDN1163 decreased hepatic citric acid cycle flux and liver pyruvate cycling, enhanced expression of mitochondrial respiratory genes, and shifted hepatocellular [NADH]/[NAD⁺] and [NADPH]/[NADP⁺] ratios to a less oxidized state, which was associated with elevated PUFA content of liver lipids. In sum, the data demonstrate that pharmacological SERCA activation limits metabolic dysfunction-associated steatotic liver disease progression and prevents metabolic dysfunction induced by WD feeding in mice.

Keywords: calcium; citric acid cycle; hepatology; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; metabolic flux analysis; metabolism; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; polyunsaturated fatty acids; pyruvate cycling; sarcoplasmic/endoplasmic reticulum calcium-transporting ATPase.