Free fatty acids induce bile acids overproduction and oxidative damage of bovine hepatocytes via inhibiting FXR/SHP signaling.

Hepatic oxidative injury induced by free fatty acids (FFA) and metabolic disorders of bile acids (BA) increase the risk of metabolic diseases in dairy cows during perinatal period. However, the effects of FFA on BA metabolism remained poorly understood. In present study, high concentrations of FFA caused cell impairment, oxidative stress and BA overproduction.

Expression of hepatic genes involved in bile acid metabolism in dairy cows with fatty liver.

Bile acids are cholesterol-derived molecules that are primarily produced in the liver. In nonruminants with fatty liver, overproduction of bile acids is associated with liver injury. During the transition period, fatty liver is a metabolic disorder that can affect up to 50% of high-producing dairy cows.

Evaluation of hepatic AMPK, mTORC1, and autophagy-lysosomal pathway in cows with mild or moderate fatty liver.

The aim of the present study was to investigate the activity of AMPK and mTORC1 as well as TFEB transcriptional activity and autophagy-lysosomal function in the liver of dairy cows with mild fatty liver (FL) and cows with moderate FL. Liver and blood samples were collected from healthy dairy cows (n = 10; hepatic triglyceride content <1% wet weight) and cows with mild FL (n = 10; 1% ≤ hepatic triglyceride content < 5% wet weight) or moderate FL (n = 10; 5% ≤ hepatic triglyceride content < 10% wet weight) that had a similar number of lactations (median = 3, range = 2-4) and days in milk (median = 6 d, range = 3-9). Blood parameters were determined using a Hitachi 3130 autoanalyzer with commercially available kits.

Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis.

Ketosis occurs most frequently in the peripartal period and is associated with liver injury and steatosis. Lysosomes serve as the terminal degradative station and contribute to liver homeostasis through their role in the digestion of dysfunctional organelles and lipid droplets. Transcription factor EB (TFEB) has been identified as a master regulator of lysosomal function.

Free fatty acids impair autophagic activity and activate nuclear factor kappa B signaling and NLR family pyrin domain containing 3 inflammasome in calf hepatocytes.

Free fatty acids (FFA)-induced hepatic inflammation agravates liver injury and metabolic dysfunction in dairy cows with ketosis or fatty liver. Under stressful conditions, autophagy is generally considered as a cell protection mechanism, but whether the FFA-induced inflammatory and stress effect on hepatocytes involves an autophagy response is not well known. Thus, the objective of this study was to investigate the effects of FFA on autophagy and the role of autophagy in the activation of NF-κB (nuclear factor kappa B) signaling and NLRP3 (NLR family pyrin domain containing 3) inflammasome in calf hepatocytes.

Propionate alleviates palmitic acid-induced endoplasmic reticulum stress by enhancing autophagy in calf hepatic cells.

Negative energy balance-induced high blood concentrations of free fatty acids during the early postpartum period in dairy cows is a major cause of liver injury. Cows in severe negative energy balance often have suboptimal intakes of feed, which contributes to shortfalls in production of ruminal propionate and circulating glucose. Although increasing propionate production by the rumen through feed additives such as propylene glycol is effective in helping cows alleviate the shortfall in dietary energy supply, mechanisms whereby propionate affects liver function beyond gluconeogenesis are unknown.

Hepatic autophagy and mitophagy status in dairy cows with subclinical and clinical ketosis.

Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are important processes responsible for breaking down useless or toxic cellular material, and in particular damaged mitochondria. However, the role of autophagy and mitophagy during the occurrence and development of ketosis is unclear.