Abstract
A high-fat “Western-style” diet (HFWD) promotes obesity-related conditions including non-alcoholic steatohepatitis (NASH), the histologic manifestation of non-alcoholic fatty liver disease (NAFLD). In addition to high saturated fat and processed carbohydrates, the typical HFWD is deficient in calcium. Calcium-deficiency is an independent risk factor for many conditions associated with the Western-style diet. However, calcium has not been widely evaluated in the context of NAFLD. The goal of the present study was to determine if dietary calcium supplementation could protect mice fed a HFWD from NAFLD, specifically by decreasing non-alcoholic steatohepatitis (NASH) and its down-stream consequences. Male C57BL/6NCrl mice were maintained for 18-months on a HFWD containing dietary calcium at either 0.41 gm/kg feed (unsupplemented) or 5.25 gm/kg feed (supplemented). Although there was no difference in body weight or steatosis, calcium-supplemented mice were protected against downstream consequences of hepatic steatosis, manifested by lower inflammation, less fibrosis, and by lower overall histologic NAFLD activity scores (NAS). Calcium supplementation correlated with distinctly segregating gut fecal and cecal microbial communities as defined by 16S rRNA gene sequence. Further, calcium supplementation also correlated with decreased hepatic concentration of the major conjugated murine primary bile acid, tauro-β-muricholic acid (as well as a decrease in the parent unconjugated bile acid). Thus, calcium was protective against progression of diet-induced hepatic steatosis to NASH and end-stage liver disease, suggesting that calcium supplementation may effectively protect against adverse hepatic consequences of HFWD in cases where overall diet modification cannot be sustained. This protective effect occurred in concert with calcium-mediated gut microbial community shifts and alterations of the hepatic bile acid pool.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a common consequence of obesity and metabolic syndrome [1,2] and is rapidly increasing in Western society [3,4,5]
Dietary caloric restriction to reduce steatosis is a mainstay of NAFLD prevention, but its efficacy is hampered by poor compliance and potentially by early life metabolic and gut microbial alterations that have prolonged inhibitory effects on weight loss [4]
In this study we demonstrated that calcium supplementation ameliorated liver injury and generated relevant alterations of gut microbes and bile acids but did not affect weight gain
Summary
Non-alcoholic fatty liver disease (NAFLD) is a common consequence of obesity and metabolic syndrome [1,2] and is rapidly increasing in Western society [3,4,5]. While steatosis is generally welltolerated, in some individuals there is progression to non-alcoholic steatohepatitis (NASH), consisting of inflammatory foci and characteristic ballooning degeneration of hepatocytes. Ensuing cycles of hepatocellular injury and regeneration lead to fibrosis and, eventually, cirrhosis, which is an end-stage state characterized by widespread inflammation, fibrotic scarring and formation of regenerative hyperplastic nodules [5,6,7,8]. NAFLD is rapidly becoming the most common cause of chronic liver injury in industrialized countries, in parallel with the increased consumption of a high fat, “Western-style” diet (HFWD) [3,4]. Since steatosis alone is well-tolerated, there may be significant benefit to pharmaceutical or nutraceutical interventions acting at downstream points in the progression from steatosis to the pathologic states of NASH and cirrhosis
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