Malnutrition induces steatohepatitis by impairing hepatic lipid metabolism, mitochondrial function and the gut-liver axis.

Abstract

Malnutrition of protein and essential nutrients in children can lead to serious health problems. It significantly alters hepatic physiology and leads to impaired liver function. The present study investigated the underlying mechanism of malnutrition-induced steatohepatitis in a rat model. Weanling rats were divided into two groups. The control rats received a standard protein diet, while the other group was fed a low protein diet (LPD) for eight weeks. LPD significantly reduced the body and liver weights and altered the blood parameters. LPD resulted in elevated serum liver injury markers and lowered glucose, albumin, and total protein levels. The reduced levels of TIBC and TSI and upregulated expression of Hamp gene were observed in the LPD group. Histopathology revealed the severe fat accumulation in the hepatocytes, leading to inflammation and fibrognesis. LPD upregulated the de novo lipogenesis (Srebp1c, Fas, Acc, and Scd1) markers and oxidative stress in the hepatic tissue. The downregulation of Pgc1α, Tim23, and Tfam indicated mitochondrial dysfunction in the LPD group. Transcriptomic analysis revealed the upregulation of 7,545 genes in the LPD group mainly associated with metabolic dysfunction-associated steatotic liver disease (MASLD), beta-oxidation, AMPK signalling and oxidative phosphorylation. Hepatic lipidome revealed the elevated levels of various lipid species in the LPD group. Further, LPD altered the gut microbiome of rats and reduced the relative abundance of beneficial bacteria. The present study revealed that malnutrition induces hepatic steatoheptitis by altering the hepatic lipid metabolism and disrupting mitochondrial function and gut-liver axis.