Background and Purpose Non‐alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis. Experimental Approach In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high‐fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum–mitochondrial linker was adopted to increase mitochondria‐associated membranes (MAMs) and MICU1‐EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel. Key Results Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD‐induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high‐calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD‐induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01‐μM·kg−1 bodyweight) can alleviate HFD‐induced hepatic steatosis. Conclusion and Implications These findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.

The small intestine is main site of exogenous lipid digestion and absorption, and it is important for lipid metabolic homeostasis. Cell death-inducing DNA fragmentation-factor like effector C (CIDEC) is active in lipid metabolism in tissues other than those in the intestine. We developed small intestine-specific CIDEC (SI-CIDEC -/- ) knockout C57BL/6J mice by Cre/LoxP recombination to investigate the in vivo effects of intestinal CIDEC on lipid metabolism. Eight-week-old SI-CIDEC -/- mice fed a high-fat diet for 14 weeks had 15% lower body weight, 30% less body fat mass, and 79% lower liver triglycerides (TG) than wild-type (WT) mice. In addition, hepatic steatosis and fatty liver inflammation were less severe in knockout mice fed a high-fat diet (HFD) compared with wild-type mice fed an HFD. SI-CIDEC -/- mice fed an HFD diet had lower serum TG and higher fecal TG and intestinal lipase activity than wild-type mice. Mechanistic studies showed that CIDEC accelerated phosphatidic acid synthesis by interacting with 1-acylglycerol-3-phosphate-O-acyltransferase to promote TG accumulation. This study identified a new interacting protein and previously unreported CIDEC mechanisms that revealed its activity in lipid metabolism of the small intestine.

As living standards improve, obesity has become an increasingly serious health problem. Natural extracts from a wide range of sources are non-toxic and have significant potential as drugs for the...

Metabolic associated fatty liver disease is the main cause of chronic liver disease in the world, but there is still no effective treatment.

Long‐term high‐fat diet (HFD) will lead to obesity and their complications. Echinocystic acid (EA), a triterpene, shows anti‐inflammatory and antioxidant effects. We predict that EA supplementation can prevent obesity, diabetes, and nonalcoholic steatohepatitis. To test our hypothesis, we investigated the effects of EA supplementation on mice with HFD‐induced obesity in vivo and in vitro by adding EA to the diet of mice and the medium of HepG2 cells, the protein target of EA was analyzed by molecular docking. The results showed that EA ameliorated obesity and inhibited blood triglyceride and liver triglyceride concentrations than those in the HFD groups. The data on molecular docking indicated that FABP1 was a potential target of EA. Further experimental results confirmed that EA affected the triglyceride level by regulating the function of FABP1. This study may provide a new potential inhibitor for FABP1 and a new strategy for the treatment of obesity.